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Contents lists available at ScienceDirect
Brain Research Bulletin journal homepage: www.elsevier.com/locate/brainresbull
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Review
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RIFAMPICIN: An antibiotic with brain protective function
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Burak Yulug a,∗ , Lütfü Hanoglu a , Ertugrul Kilic b , Wolf Rüdiger Schabitz c a
Department of Neurology, University of Istanbul-Medipol, Istanbul, Turkey Department of Physiology, Brain Research Laboratory, University of Istanbul-Medipol, Istanbul, Turkey c Department of Neurology, Bethel-EvKB, Bielefeld, Germany
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b
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Article history: Received 11 March 2014 Received in revised form 8 May 2014 Accepted 27 May 2014 Available online xxx
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Besides its well known antibiotic activity rifampicin exerts multiple brain protective functions in acute cerebral ischemia and chronic neurodegeneration. The present mini-review gives an update of the unique activity of rifampicin in different diseases including Parkinson’s disease, meningitis, stroke, Alzheimer’s disease and optic nerve injury. © 2014 Elsevier Inc. All rights reserved.
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Keywords: Rifampicin Stroke Parkinson’s disease Alzheimer’s disease Optic nerve injury Meningitis
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Contents
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Meningitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. Optic nerve injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4. Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5. Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.6. The effects of rifampicin on glucocorticoid receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction
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The overwhelming progress in basic neuroscience research led to many therapeutic advances for neurological diseases. Despite these achievements treatment opportunities for several diseases such as stroke or dementia are still devastating. Therefore, research focused on the development of novel candidates causally interacting in brain disease pathophysiology. Of these candidates, antibiotics are particularly interesting because they exert in addition
∗ Corresponding author. Tel.: +90 506 406 97 14; fax: +90 232 446 80 90. E-mail address: [email protected] (B. Yulug).
to the substance immanent antibiotic activity an array of brain protective functions including the prevention of mitochondrial mediated cytochrome c release, microglial activation, glutamate neurotoxicity, and oxidative stress (Kim and Suh, 2009; Hashimoto, 2008; Mao, 2005; Rothstein et al., 2005; Tomiyama et al., 1996a). Rifampicin is a semisynthetic derivative of the rifampycins, a class of broad-spectrum antibiotics that are fermentation products of Nocardia meditterranei. The common structure of the rifampycins is a napthohydroquinone chromophore spanned by an aliphatic ansa chain (Tomiyama et al., 1996a). Rifampicin reaches maximal serum concentration in 1–4 h after application and its plasma half-time is 2–5 h (Acocella, 1978). The lipophilic ansa chain is mainly responsible for the transport of the drug across the blood-brain barrier (BBB) into the brain parenchyma (Mindermann et al., 1993). In the light
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of increasing evidences of oxidative stress and recently defined immunological cell death pathways in both acute and chronic neurodegenerative diseases the present review gives an update on the brain protective functions of rifampicin in the major diseases. 1.1. Stroke Stroke is the third leading cause of death and adult morbidity in developed countries (Sudlow and Warlow, 1997; Rothwell, 2001). Many molecular mechanisms including the role of massive inflammation and oxidative injury have been proposed to explain the pathogenesis of this clinically devastating disease (Bowen et al., 2006; Dirnagl et al., 1999; Hal et al., 1997). Poststroke reperfusion leads to free radical accumulation and release which damages intracellular and extracellular membranes ultimately resulting in cell dysfunction and death. The latter one damages intracellular and extracellular membranes ultimately resulting in cell dysfunction and death (Calleja et al., 1998). This concept was confirmed by various studies establishing the neuroprotective efficacy of free-radical scavengers after cerebral ischemia (Hal et al., 1997). The structural feature of rifampicin suggests that this drug may function as a free radical scavenger with its naphthohydroquinone ring which may contribute to the function of a hydroxyl radical scavenger activities in inhibiting neurotoxicity (Tomiyama et al., 1996a; Hal et al., 1997). Furthermore, rifampicin has been shown to downregulate the expression of pro-apoptotic Bax and upregulate the expression of anti-apoptotic Bcl-2, Bcl-XL, and of anti-apoptotic gene products such as XIAP, cIAP2, FLIPs, which play essential roles to block ischemia-mediated cell death (Gollapudi et al., 2003; Kilic et al., 2004; Jing et al., 2014; Notarianni, 2013). In this respect, we have earlier shown that rifampicin efficiently reduced brain injury and increased the number of viable neurons after permanent and transient focal cerebral ischemia in mice (Jing et al., 2014). All these findings suggest that rifampicin may be particularly suited for the treatment of stroke, where both kinds of injury interfere or overlap with each other. Rifampicine may therefore be an ideal candidate because it counteracts infections in acute stroke and acts at the same time as neuroprotectant 1.2. Meningitis Despite an effective antibiotic therapy, bacterial meningitis is still associated with high rates of mortality and permanent sequelae in children and adults (Mustafa et al., 1989). It is widely known that bacterial compounds release the production of reactive oxygen species (ROS), proinflammatory cytokines, excitatory amino acids and induce meningeal inflammation (Leib et al., 1996a,b; Mawatari et al., 1996; Tumani et al., 2000). Additionally, the functional relationship between oxidative injury and excitotoxicity has been established in several in vitro studies (Reynolds and Hastings, 1995). Radical scavengers were, for example, shown to attenuate early pathophysiological changes in bacterial meningitis (Koedel and Pfister, 1999; Böttcher et al., 2000). However, the inflammatory host response after initiation of therapy with antibiotics currently used for meningitis may contribute to early mortality and longterm sequelae in bacterial meningitis (Nau et al., 1999; Böttcher et al., 2000). Antibiotics can lead to the release of proinflammatory components of the bacterial cell wall into cerebrospinal fluid (CSF) during bacterial lysis which can secondary cause a burst of meningeal inflammation (Böttcher et al., 2000; Mustafa et al., 1989; Nau et al., 1997) and injury to the host including loss of membrane function, DNA damage, and cell death (Leib et al., 1996a; Koedel and Pfister, 1999; Böttcher et al., 2000). In this respect, both in vitro and in vivo studies have demonstrated that antibiotics that act by inhibiting protein synthesis, such as rifampin and rifabutin,
release smaller quantities of lipoteiochic acids (LTA)/teichoic acids (TA) than b-lactam antibiotics (Nau et al., 1999; Stuertz et al., 1998). Nau et al. compared by their interesting study the effects of rifampicin with those of ceftriaxone on mortality, neuronal damage, and LTA-TA concentrations in serum and CSF in a model of experimental meningitis in mice (Nau et al., 1999). After intracerebral infection with S. pneumoniae they applied 2-mg doses of rifampicin or ceftriaxone and demonstrated that rifampicin not only reduced overall mortality during the first 24 h but led to a significant decrease of serum and cerebrospinal fluid concentrations of proinflammatory bacterial compounds compared to ceftriaxone-treated mice. This study confirmes previous data from a rabbit model of pneumococcal meningitis comparing the effect of rifampicin versus ceftriaxone on ROS production of CSF phagocytes, on CSF malondialdehyde (MDA) concentrations, and on neuronal damage. The study suggests that CSF leukocytes from rifampicin-treated rabbits produced less ROS than leukocytes from animals treated with ceftriaxone (Böttcher et al., 2000). Böttcher et al. (2000) interestingly found that the CSF malondialdehyde concentrations and the density of apoptotic neurons in the dentate gyrus were lower after rifampicin than ceftriaxone-treated animals providing further evidence that minimizing the release of proinflammatory bacterial compounds may improve outcome in bacterial meningitis. Favoring the therapeutic role of antibiotics that do not interfere with cell wall synthesis, these findings were suggested with two earlier studies showing that rifabutin and quinupristin–dalfopristin inhibited the rise of tumor necrosis factor in CSF compared with ceftriaxone therapy (Schmidt et al., 1997; Trostdorf et al., 1999). This was suggested by recent human studies showing that intensified treatment with high dose rifampicin could be associated with better survival in patients with tuberculous meningitis (Yulug et al., 2004; Ruslami et al., 2013) In conlusion, with its radical scavenging and immunomodulating efficacy, rifampicin represents an interesting therapeutic candidate for reducing early mortality in bacterial meningitis. 1.3. Optic nerve injury Optic nerve injury models provide valuable opportunities to discover and study mechanisms of axotomy induced retinal ganglion cell apoptosis and allowed the evaluation of several potential strategies for neuroprotection in neurodegenerative diseases. It has been shown that transection of the optical nerve (ON) triggers a highly coordinated response of injury-associated genes, which finally leads to apoptosis of retinal ganglion cells (RGC) (Kilic et al., 2004; Isenmann et al., 1997; Klocker et al., 1998). In neurodegenerative disease, it is widely known that production of reactive oxygen species overwhelm endogenous antioxidant defense mechanisms hereby inducing neuronal cell death. In this respect, antioxidant agents were shown to suppress apoptosis induced by various insults, including axotomy (Kilic et al., 2004; Castagne and Clarke, 1996). The free radical–scavenger activity of rifampicin has been shown by electron spin resonance spectrometric analysis and stable free radical alpha, alpha-diphenylbeta-picrylhydrazyl (DPPH) reduction (Kilic et al., 2004; Karunakar et al., 2003; Namba et al., 1992). Beyond the antioxidative properties of rifampicin, several other neuroprotective mechanisms have been discussed. Gollapudi et al. (2003) who reported that rifampicin-mediated inhibition of apoptosis and activation of caspase-3 and capase-8 occurred at least in part via Glucocorticoid receptor (GR) activation. Additionally, it has been already shown that rifampicin may block programmed cell death through various pro- and anti-apoptotic proteins (Gollapudi et al., 2003; Kilic et al., 2004; Jing et al., 2014; Notarianni, 2013). In the light of these findings, we have earlier evaluated the possible neuroprotective effect of rifampicin comparing the vehicle and rifampicin treated mice after axotomy of mice (Kilic et al.,
Please cite this article in press as: Yulug, B., et al., RIFAMPICIN: An antibiotic with brain protective function. Brain Res. Bull. (2014), http://dx.doi.org/10.1016/j.brainresbull.2014.05.007
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2004). After continious administration of 5 mg/kg rifampicin during the subsequent 14 days of axotomy we have evaluated the survival of RGCs by fluorescence microscopy and demonstrated that in the rifampicin treated group, retinal ganglion cell survival was significantly increased after axotomy as compared with vehicle treated and phosphate-buffered saline treated control animals. These findings altogether suggest that rifampicin is able to prevent neuronal cell degeneration including anti-oxidative and anti-apoptotic mechanisms suggesting a potential role for future treatment of neurodegenerative disorders.
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1.4. Parkinson’s disease
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proven regulatory effect on human glucocorticoid receptor and gene expression (Calleja et al., 1998), the immunomodulatory role of rifampicin has been suggested by a recent study showing that rifampicin may suppress nuclear factor-kappa B that may be responsible for decreasing toll-like receptor 2 (TLR2) (Kim et al., 2009) and phosphorylation of mitogen-activated protein kinases (MAPKs) (Bi et al., 2013; Molloy et al., 2013). All these findings support the potential role of rifampicin as a novel anti-inflammatory drug for the treatment of PD. 1.5. Alzheimer’s disease
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Parkinson’s disease (PD) leads to degeneration of dopaminergic neurons in the substantia nigra pars compacta and the deposition of Lewy bodies in surviving neurons (Langston, 2002; Heisters, 2011; Eriksen et al., 2005; Babi and Mahovi, 2008; Bi et al., 2013). Many different factors and pathways have been hypothesized in the pathogenesis of neuronal death in PD including oxidative stress, mitochondrial dysfunction, neuroinflammation, and apoptosis (Bi et al., 2013; Olanow, 2007). It has been already shown that 1methyl-4-phenylpyridinium (MPP+) exerts its neurotoxic actions by inhibition of the complex I activity and induction of lipid peroxidation that has been shown to be associated with activation of apoptosis (Bi et al., 2013; Watanabe et al., 2005). In the light of these findings, we have earlier evaluated the neuroprotective effects of rifampicin on dopaminergic neuron survival in an in vivo model of MPP+ intoxication (Kilic et al., 2004). We found that rifampicin at different concentrations significantly increased the number of surviving dopaminergic neurons which was suggested by a similar study by Oida et al. (Bi et al., 2013; Oida et al., 2006). Dopaminergic toxicity of MPP may be associated with an upregulation of oligomeric species of alpha-synuclein (Bi et al., 2013; Xu et al., 2007) suggesting the role of alpha-synuclein aggregation by mitochondrial dysfunction in PD pathogenesis. This was in agreement with other studies demonstrating that upregulation of alphasynuclein increases cytotoxicity and neurodegeneration (Bennett, 2005). In this respect, Xu et al. demonstrated that rifampicin pretreatment led to a dose-dependent increase in cell viability and reduction in alpha-synuclein expression (Xu et al., 2007) as suggested by previous data showing that rifampicin inhibits alphasynuclein fibrillation and disaggregates existing fibrils (Li et al., 2004). Rifampicin’s neuroprotective effect was further suggested by earlier in vitro studies showing its free radical scavenging activity (Tomiyama et al., 1996a). These studies supported the important role of mitochondria as the major source of ROS responsible for oxidative stress-mediated cell death in PD (Beal, 1992; Adams et al., 2001). In a study by Chen et al. rifampicin pretreatment protects PC12 cells against rotenone-induced cell death by suppressing rotenone-induced apoptosis and mitochondrial oxidative stress (Chen et al., 2010). However the molecular mechanism underlying this neuroprotection remain unknown. In this respect, a very recent proteomic analysis study has shown that rifampicin exerted protective cellular responses via the up regulation of glucose-regulated protein 78 which is a chaperone protein localized in the endoplasmic reticulum and plays important role in cytoprotection and cell survival under endoplasmic stress in response to accumulation of misfolded proteins (Bi et al., 2011) Increasing evidence has demonstrated that also neuroinflammation, which is characterized by activated microglia and infiltrating T cells at the sites of neuronal injury, plays an important role in the pathophysiology of PD (Bi et al., 2013; Qian et al., 2010; Lu et al., 2010). Investigations using lypopolysacharide-stimulated BV2 microglial cells demonstrated that rifampicin significantly inhibited the LPS-induced expression of pro-inflammatory mediators (Bi et al., 2013; Dutta et al., 2008). Besides rifampicin’s
Alzheimer’s disease (AD) is a progressive neurodegenerative disease, one primary cause of a progressive decline of cognitive and memory functions ultimatively leading to dementia. The neuropathological correlates of the disease are the occurrence of extracellular senile plaques and intracellular neurofibrillary tangles leading to neuronal death and brain atrophy (Schaeffer et al., 2011; Philipson et al., 2010; Hardy and Higgins, 1992; Estus et al., 1997). Beta amyloid (A) was shown to be a key factor in AD pathogenesis inducing and maintaining pathophysiological processes such as neuroinflammation, excitotoxixity, oxidative stress, tau hyperphosphorilation and A aggregation (Morrison and Lyketsos, 2005; Dyrks et al., 1992). The generation of A from Amyloid-Precursor-Protein (APP) is a complex pathway and involving enzymatic cleavage of transmembrane APP protein. This may result in amyloid accumulation secondary to an imbalance between protein fragment production and its clearance (Schaeffer et al., 2011; Philipson et al., 2010; Hardy and Higgins, 1992; Estus et al., 1997; Cummings, 2004; Morrison and Lyketsos, 2005). Besides its well known pathophysiological role by various neurodegenerative diseases, earlier studies further demonstrated that free radical production is also involved in the generation of A aggregation (Dyrks et al., 1992; Hensley et al., 1994) suggesting a potential inhibiting role of radical scavengers on A related neurotoxicity. Tomiyama et al. reported that rifampicin inhibited aggregation and fibril formation of synthetic A 1–40 peptide and related neurotoxicity in a dose-dependent manner on rat pheochromocytoma PC12 cells (Tomiyama et al., 1994, 1996b). This suggested that at least one mechanism of rifampicin-mediated inhibition of A aggregation may include scavenging of free radicals and supported a potential therapeutic role of rifampicin for Alzheimer’s disease. Rifampicin may exert its neuroprotective effects in addition to scavenging free radicals by inhibition of amyloid fibril formation (Tomiyama et al., 1997). In accordance with these studies recent evidence strongly suggests that impaired clearance of A across the BBB might lead to the formation of A brain deposits and Alzheimer’s disease progression (Endoh et al., 1999; Cirrito et al., 2005; Vogelgesang et al., 2002; Kuhnke et al., 2007; Lam et al., 2001). Thus, the efflux transporter permeability glycoprotein (P-gp) may play an important role for the elimination of A1–40 and A1–42 from the brain across the BBB (Endoh et al., 1999; Cirrito et al., 2005; Vogelgesang et al., 2002; Kuhnke et al., 2007; Lam et al., 2001). Abuznait et al. demonstrated that decreased intracellular accumulation of A1–40 is associated with P-gp up-regulation caused by rifampicin (Lam et al., 2001). These findings were consistent with their results on an in vitro concentration-dependent increase in Pgp expression and activity by various drugs, including rifampicin (Abuznait et al., 2011a). Moreover, a very recent mice study has shown that the upregulation of Low density lipoprotein receptorrelated protein 1 (LRP1) and P-gp at the BBB by rifampicin and caffeine enhanced brain A clearance and suggested the presence of a possible transporter/receptor that plays an important role in A clearance which is upregulated by rifampicin (Abuznait et al., 2011b). All these findings together support a possible relationship between P-gp dysregulation and cognitive improvement in
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Table 1 Summary of positive trials of rifampicin treatment for neuroprotection. Disease
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Outcome
Study
Source
Animal
Human
Stroke
↓ Infarct volumes ↓ Apoptotic cell death
+
−
Yulug et al. (2004)
Menengitis
↓ Neuronal damage ↓ Proinflamatory mediators ↓ ROS production ↓ Mortality ↑ Clinical survival
+
+
Nau et al. (1999) Böttcher et al. (2000) Stuertz et al. (1998) Schmidt et al. (1997) Trostdorf et al. (1999) Ruslami et al. (2013) Alvarez-Uria et al. (2013)
Optic nerve injury
↓ Apoptotic retinal ganglion cell death
+
−
Kilic et al. (2004)
Parkinson’s disease
↑ Dopaminergic cell survival ↓ Alpha synuclein expression ↑ GRP78 expression ↓ MPP+-induced apoptosis
+
−
Kilic et al. (2004) Oida et al. (2006) Xu et al. (2007) Li et al. (2004) Chen et al. (2010) Jing et al. (2014)
Alzheimer’s disease
↓ Amyloid Beta aggregation ↑ Amyloid Beta clearance ↑ P-gp Improved clinical SADAScog score
+
+
Tomiyama et al. (1994, 1997) Abuznait et al. (2011a) Qosa et al. (2012) Loeb et al. (2004) Namba et al. (1992)
patients with Alzheimer’s disease suggesting that in addition to oxidative injury and fibril aggregation, targeting P-gp by rifampicin could be an effective strategy in decreasing the progression of Alzheimer’s disease. In contrast to the rapidly increasing preclinical data, only a few clinical studies evaluated the effects of rifampicin in patients with Alzheimer’ disease. Namba et al. reported by their recent study that non-demented elderly leprosy patients that were on rifampicine treatment for years showed an unusual absence of senile plaques in their brains compared with age-matched controls (Namba et al., 1992). Another study by Loeb et al. showed that oral daily doses of rifampin 300 mg for 3 months in patients with
mild to moderate AD improved cognitive function measured with the Standardized Alzheimer’s Disease Assessment Scale-Cognitive Subscale (SADAScog score) (Qosa et al., 2012). However, these promising pilot results could not be replicated in a recent study were patients were treated twelve months with rifampicin (Loeb et al., 2004). Overall, despite strong preclinical evidences this controversial clinical findings together suggest that more clinical research and related functional neuroimaging data (etc. amyloidPET) with combined clinical assessment scores is needed in order to investigate the clinical relevance of the neuroprotective effect of Q4 rifampicin (Table 1 and Fig. 1).
Anti-apoptotic
Anti-inflamatory
•Stimulates anti-apoptotic Bcl-2, Bcl-XL, XIAP, CIAP2 and FLIP activities
•Reduces pro-inflamatory cytokines and bacterial compounds
•Reduces pro-apoptotic Bax, Caspase 3 and caspase 8 activities
•Reduces NF B, MAPKs and TLR-2 activities •Increases GR agonist activity
•Increases eNOS activity
Rifampicin
Anti-oxidant
Anti-Alzheimer
•Reduces ROS production
•Reduces A β aggregation
•Reduces mitochondrial oxidative stress
•Reduces amyloid fibril formation •Increases permeability glycoprotein
Anti-Parkinson •Reduces MPP + toxicity •Reduces alpha-synuclein aggregation •Increases glucose-regulated protein 78 Fig. 1. Multiple mechanisms of rifampicin.
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Besides studies suggesting free radical scavenging as a potential neuroprotective mechanism of rifampicin, earlier studies have further shown that rifampicin can also activate glucocorticoid receptors (Calleja et al., 1998). Despite conflicting reports regarding the protective role of corticosteroids (Wallerath et al., 1999), the activation of glucocorticoid receptors has been shown not only to mediate neuroprotection but also exert to myocardioprotective effects mediated by nontranscriptional activation of endothelial nitric oxide synthase (eNOS) through the PI3K/Akt pathway (Hafezi-Moghadam et al., 2002). Additionally, high-dose corticosteroids given within 2 h of transient cerebral ischemia were shown to increase eNOS activity, augment regional cerebral blood flow and reduce cerebral infarct size abolished by treatment with the glucocorticoid receptor (GR) antagonist (Limbourg et al., 2002). This was suggested by Gollapudi et al. (2003) who reported rifampicinmediated inhibition of peripheral blood T lymphocyte apoptosis via GR activation which was associated by inhibition of activation of both caspase-3 and caspase-8 and reversed by GR antagonist (RU486). However rifampicin’s agonist activity on the glucocorticoid receptor may function also as an immunodepressor that can help to decrease host related neuronal damage by neuroinflamation (Calleja et al., 1998; Nau et al., 1999). Additionally, recent studies showed that rifampicin may lead to induction of gene transcription controlled by glucocorticoid receptor- binding elements (Calleja et al., 1998) which were shown to exist in isolated Müller and photoreceptor cells in intact salamander retina and in all cell types in the human eye (Psarra et al., 2003). Activated GRs can inhibit activator protein (AP-1), which is essential for the induction of photoreceptor apoptosis by light and GR-mediated inhibition may occur in the nucleus of retinal cells by a protein- protein interaction of both transcription factors. Thus, induction of GR activity has been shown to prevent light-induced retinal degeneration by interference with AP-1-dependent steps of apoptosis induction in mice (Wenzel et al., 2001). Furthermore regarding recent hypothesis suggesting the role of neuroinflamation related glucocorticoid receptor-signaling insufficiency in the development of Alzheimer’s disease, rifampicin may play an important role in the progress of the disease via the activation of glucocorticoid receptors (Alvarez-Uria et al., 2013).
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2. Conclusion
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The antibiotic rifampicin exerts strong brain protective in various in vivo and in vitro models of neurodegenerative disease including Stroke, Parkinson’s, Alzheimer’s. Pilot clinical studies suggest that patients with neurodegenerative diseases may benefit from rifampicin treatment. These promising findings should be further explored in larger preclinical therapeutic studies and further on in randomized early phase clinical trials. Uncited reference Yerramasetti et al. (2002). References Abuznait, A.H., Cain, C., Ingram, D., Burk, D., Kaddoumi, A., 2011a. Up-regulation of Pglycoprotein reduces intracellular accumulation of beta amyloid: investigation of P-glycoprotein as a novel therapeutic target for Alzheimer’s disease. J. Pharm. Pharmacol. 63, 1111–1118. Abuznait, A.H., Patrick, S.G., Kaddoumi, A., 2011b. Exposure of LS-180 cells to drugs of diverse physicochemical and therapeutic properties up-regulates Pglycoprotein expression and activity. J. Pharm. Pharm. Sci. 14, 236–248. Acocella, G., 1978. Clinical pharmacokinetics of rifampicin. Clin. Pharmacokinet. 3, 108–127.
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Contents lists available at ScienceDirect
Brain Research Bulletin journal homepage: www.elsevier.com/locate/brainresbull
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Review
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RIFAMPICIN: An antibiotic with brain protective function
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Burak Yulug a,∗ , Lütfü Hanoglu a , Ertugrul Kilic b , Wolf Rüdiger Schabitz c a
Department of Neurology, University of Istanbul-Medipol, Istanbul, Turkey Department of Physiology, Brain Research Laboratory, University of Istanbul-Medipol, Istanbul, Turkey c Department of Neurology, Bethel-EvKB, Bielefeld, Germany
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Article history: Received 11 March 2014 Received in revised form 8 May 2014 Accepted 27 May 2014 Available online xxx
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Besides its well known antibiotic activity rifampicin exerts multiple brain protective functions in acute cerebral ischemia and chronic neurodegeneration. The present mini-review gives an update of the unique activity of rifampicin in different diseases including Parkinson’s disease, meningitis, stroke, Alzheimer’s disease and optic nerve injury. © 2014 Elsevier Inc. All rights reserved.
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Keywords: Rifampicin Stroke Parkinson’s disease Alzheimer’s disease Optic nerve injury Meningitis
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Contents
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Meningitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. Optic nerve injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4. Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5. Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.6. The effects of rifampicin on glucocorticoid receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction
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The overwhelming progress in basic neuroscience research led to many therapeutic advances for neurological diseases. Despite these achievements treatment opportunities for several diseases such as stroke or dementia are still devastating. Therefore, research focused on the development of novel candidates causally interacting in brain disease pathophysiology. Of these candidates, antibiotics are particularly interesting because they exert in addition
∗ Corresponding author. Tel.: +90 506 406 97 14; fax: +90 232 446 80 90. E-mail address: [email protected] (B. Yulug).
to the substance immanent antibiotic activity an array of brain protective functions including the prevention of mitochondrial mediated cytochrome c release, microglial activation, glutamate neurotoxicity, and oxidative stress (Kim and Suh, 2009; Hashimoto, 2008; Mao, 2005; Rothstein et al., 2005; Tomiyama et al., 1996a). Rifampicin is a semisynthetic derivative of the rifampycins, a class of broad-spectrum antibiotics that are fermentation products of Nocardia meditterranei. The common structure of the rifampycins is a napthohydroquinone chromophore spanned by an aliphatic ansa chain (Tomiyama et al., 1996a). Rifampicin reaches maximal serum concentration in 1–4 h after application and its plasma half-time is 2–5 h (Acocella, 1978). The lipophilic ansa chain is mainly responsible for the transport of the drug across the blood-brain barrier (BBB) into the brain parenchyma (Mindermann et al., 1993). In the light
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of increasing evidences of oxidative stress and recently defined immunological cell death pathways in both acute and chronic neurodegenerative diseases the present review gives an update on the brain protective functions of rifampicin in the major diseases. 1.1. Stroke Stroke is the third leading cause of death and adult morbidity in developed countries (Sudlow and Warlow, 1997; Rothwell, 2001). Many molecular mechanisms including the role of massive inflammation and oxidative injury have been proposed to explain the pathogenesis of this clinically devastating disease (Bowen et al., 2006; Dirnagl et al., 1999; Hal et al., 1997). Poststroke reperfusion leads to free radical accumulation and release which damages intracellular and extracellular membranes ultimately resulting in cell dysfunction and death. The latter one damages intracellular and extracellular membranes ultimately resulting in cell dysfunction and death (Calleja et al., 1998). This concept was confirmed by various studies establishing the neuroprotective efficacy of free-radical scavengers after cerebral ischemia (Hal et al., 1997). The structural feature of rifampicin suggests that this drug may function as a free radical scavenger with its naphthohydroquinone ring which may contribute to the function of a hydroxyl radical scavenger activities in inhibiting neurotoxicity (Tomiyama et al., 1996a; Hal et al., 1997). Furthermore, rifampicin has been shown to downregulate the expression of pro-apoptotic Bax and upregulate the expression of anti-apoptotic Bcl-2, Bcl-XL, and of anti-apoptotic gene products such as XIAP, cIAP2, FLIPs, which play essential roles to block ischemia-mediated cell death (Gollapudi et al., 2003; Kilic et al., 2004; Jing et al., 2014; Notarianni, 2013). In this respect, we have earlier shown that rifampicin efficiently reduced brain injury and increased the number of viable neurons after permanent and transient focal cerebral ischemia in mice (Jing et al., 2014). All these findings suggest that rifampicin may be particularly suited for the treatment of stroke, where both kinds of injury interfere or overlap with each other. Rifampicine may therefore be an ideal candidate because it counteracts infections in acute stroke and acts at the same time as neuroprotectant 1.2. Meningitis Despite an effective antibiotic therapy, bacterial meningitis is still associated with high rates of mortality and permanent sequelae in children and adults (Mustafa et al., 1989). It is widely known that bacterial compounds release the production of reactive oxygen species (ROS), proinflammatory cytokines, excitatory amino acids and induce meningeal inflammation (Leib et al., 1996a,b; Mawatari et al., 1996; Tumani et al., 2000). Additionally, the functional relationship between oxidative injury and excitotoxicity has been established in several in vitro studies (Reynolds and Hastings, 1995). Radical scavengers were, for example, shown to attenuate early pathophysiological changes in bacterial meningitis (Koedel and Pfister, 1999; Böttcher et al., 2000). However, the inflammatory host response after initiation of therapy with antibiotics currently used for meningitis may contribute to early mortality and longterm sequelae in bacterial meningitis (Nau et al., 1999; Böttcher et al., 2000). Antibiotics can lead to the release of proinflammatory components of the bacterial cell wall into cerebrospinal fluid (CSF) during bacterial lysis which can secondary cause a burst of meningeal inflammation (Böttcher et al., 2000; Mustafa et al., 1989; Nau et al., 1997) and injury to the host including loss of membrane function, DNA damage, and cell death (Leib et al., 1996a; Koedel and Pfister, 1999; Böttcher et al., 2000). In this respect, both in vitro and in vivo studies have demonstrated that antibiotics that act by inhibiting protein synthesis, such as rifampin and rifabutin,
release smaller quantities of lipoteiochic acids (LTA)/teichoic acids (TA) than b-lactam antibiotics (Nau et al., 1999; Stuertz et al., 1998). Nau et al. compared by their interesting study the effects of rifampicin with those of ceftriaxone on mortality, neuronal damage, and LTA-TA concentrations in serum and CSF in a model of experimental meningitis in mice (Nau et al., 1999). After intracerebral infection with S. pneumoniae they applied 2-mg doses of rifampicin or ceftriaxone and demonstrated that rifampicin not only reduced overall mortality during the first 24 h but led to a significant decrease of serum and cerebrospinal fluid concentrations of proinflammatory bacterial compounds compared to ceftriaxone-treated mice. This study confirmes previous data from a rabbit model of pneumococcal meningitis comparing the effect of rifampicin versus ceftriaxone on ROS production of CSF phagocytes, on CSF malondialdehyde (MDA) concentrations, and on neuronal damage. The study suggests that CSF leukocytes from rifampicin-treated rabbits produced less ROS than leukocytes from animals treated with ceftriaxone (Böttcher et al., 2000). Böttcher et al. (2000) interestingly found that the CSF malondialdehyde concentrations and the density of apoptotic neurons in the dentate gyrus were lower after rifampicin than ceftriaxone-treated animals providing further evidence that minimizing the release of proinflammatory bacterial compounds may improve outcome in bacterial meningitis. Favoring the therapeutic role of antibiotics that do not interfere with cell wall synthesis, these findings were suggested with two earlier studies showing that rifabutin and quinupristin–dalfopristin inhibited the rise of tumor necrosis factor in CSF compared with ceftriaxone therapy (Schmidt et al., 1997; Trostdorf et al., 1999). This was suggested by recent human studies showing that intensified treatment with high dose rifampicin could be associated with better survival in patients with tuberculous meningitis (Yulug et al., 2004; Ruslami et al., 2013) In conlusion, with its radical scavenging and immunomodulating efficacy, rifampicin represents an interesting therapeutic candidate for reducing early mortality in bacterial meningitis. 1.3. Optic nerve injury Optic nerve injury models provide valuable opportunities to discover and study mechanisms of axotomy induced retinal ganglion cell apoptosis and allowed the evaluation of several potential strategies for neuroprotection in neurodegenerative diseases. It has been shown that transection of the optical nerve (ON) triggers a highly coordinated response of injury-associated genes, which finally leads to apoptosis of retinal ganglion cells (RGC) (Kilic et al., 2004; Isenmann et al., 1997; Klocker et al., 1998). In neurodegenerative disease, it is widely known that production of reactive oxygen species overwhelm endogenous antioxidant defense mechanisms hereby inducing neuronal cell death. In this respect, antioxidant agents were shown to suppress apoptosis induced by various insults, including axotomy (Kilic et al., 2004; Castagne and Clarke, 1996). The free radical–scavenger activity of rifampicin has been shown by electron spin resonance spectrometric analysis and stable free radical alpha, alpha-diphenylbeta-picrylhydrazyl (DPPH) reduction (Kilic et al., 2004; Karunakar et al., 2003; Namba et al., 1992). Beyond the antioxidative properties of rifampicin, several other neuroprotective mechanisms have been discussed. Gollapudi et al. (2003) who reported that rifampicin-mediated inhibition of apoptosis and activation of caspase-3 and capase-8 occurred at least in part via Glucocorticoid receptor (GR) activation. Additionally, it has been already shown that rifampicin may block programmed cell death through various pro- and anti-apoptotic proteins (Gollapudi et al., 2003; Kilic et al., 2004; Jing et al., 2014; Notarianni, 2013). In the light of these findings, we have earlier evaluated the possible neuroprotective effect of rifampicin comparing the vehicle and rifampicin treated mice after axotomy of mice (Kilic et al.,
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2004). After continious administration of 5 mg/kg rifampicin during the subsequent 14 days of axotomy we have evaluated the survival of RGCs by fluorescence microscopy and demonstrated that in the rifampicin treated group, retinal ganglion cell survival was significantly increased after axotomy as compared with vehicle treated and phosphate-buffered saline treated control animals. These findings altogether suggest that rifampicin is able to prevent neuronal cell degeneration including anti-oxidative and anti-apoptotic mechanisms suggesting a potential role for future treatment of neurodegenerative disorders.
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1.4. Parkinson’s disease
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proven regulatory effect on human glucocorticoid receptor and gene expression (Calleja et al., 1998), the immunomodulatory role of rifampicin has been suggested by a recent study showing that rifampicin may suppress nuclear factor-kappa B that may be responsible for decreasing toll-like receptor 2 (TLR2) (Kim et al., 2009) and phosphorylation of mitogen-activated protein kinases (MAPKs) (Bi et al., 2013; Molloy et al., 2013). All these findings support the potential role of rifampicin as a novel anti-inflammatory drug for the treatment of PD. 1.5. Alzheimer’s disease
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Parkinson’s disease (PD) leads to degeneration of dopaminergic neurons in the substantia nigra pars compacta and the deposition of Lewy bodies in surviving neurons (Langston, 2002; Heisters, 2011; Eriksen et al., 2005; Babi and Mahovi, 2008; Bi et al., 2013). Many different factors and pathways have been hypothesized in the pathogenesis of neuronal death in PD including oxidative stress, mitochondrial dysfunction, neuroinflammation, and apoptosis (Bi et al., 2013; Olanow, 2007). It has been already shown that 1methyl-4-phenylpyridinium (MPP+) exerts its neurotoxic actions by inhibition of the complex I activity and induction of lipid peroxidation that has been shown to be associated with activation of apoptosis (Bi et al., 2013; Watanabe et al., 2005). In the light of these findings, we have earlier evaluated the neuroprotective effects of rifampicin on dopaminergic neuron survival in an in vivo model of MPP+ intoxication (Kilic et al., 2004). We found that rifampicin at different concentrations significantly increased the number of surviving dopaminergic neurons which was suggested by a similar study by Oida et al. (Bi et al., 2013; Oida et al., 2006). Dopaminergic toxicity of MPP may be associated with an upregulation of oligomeric species of alpha-synuclein (Bi et al., 2013; Xu et al., 2007) suggesting the role of alpha-synuclein aggregation by mitochondrial dysfunction in PD pathogenesis. This was in agreement with other studies demonstrating that upregulation of alphasynuclein increases cytotoxicity and neurodegeneration (Bennett, 2005). In this respect, Xu et al. demonstrated that rifampicin pretreatment led to a dose-dependent increase in cell viability and reduction in alpha-synuclein expression (Xu et al., 2007) as suggested by previous data showing that rifampicin inhibits alphasynuclein fibrillation and disaggregates existing fibrils (Li et al., 2004). Rifampicin’s neuroprotective effect was further suggested by earlier in vitro studies showing its free radical scavenging activity (Tomiyama et al., 1996a). These studies supported the important role of mitochondria as the major source of ROS responsible for oxidative stress-mediated cell death in PD (Beal, 1992; Adams et al., 2001). In a study by Chen et al. rifampicin pretreatment protects PC12 cells against rotenone-induced cell death by suppressing rotenone-induced apoptosis and mitochondrial oxidative stress (Chen et al., 2010). However the molecular mechanism underlying this neuroprotection remain unknown. In this respect, a very recent proteomic analysis study has shown that rifampicin exerted protective cellular responses via the up regulation of glucose-regulated protein 78 which is a chaperone protein localized in the endoplasmic reticulum and plays important role in cytoprotection and cell survival under endoplasmic stress in response to accumulation of misfolded proteins (Bi et al., 2011) Increasing evidence has demonstrated that also neuroinflammation, which is characterized by activated microglia and infiltrating T cells at the sites of neuronal injury, plays an important role in the pathophysiology of PD (Bi et al., 2013; Qian et al., 2010; Lu et al., 2010). Investigations using lypopolysacharide-stimulated BV2 microglial cells demonstrated that rifampicin significantly inhibited the LPS-induced expression of pro-inflammatory mediators (Bi et al., 2013; Dutta et al., 2008). Besides rifampicin’s
Alzheimer’s disease (AD) is a progressive neurodegenerative disease, one primary cause of a progressive decline of cognitive and memory functions ultimatively leading to dementia. The neuropathological correlates of the disease are the occurrence of extracellular senile plaques and intracellular neurofibrillary tangles leading to neuronal death and brain atrophy (Schaeffer et al., 2011; Philipson et al., 2010; Hardy and Higgins, 1992; Estus et al., 1997). Beta amyloid (A) was shown to be a key factor in AD pathogenesis inducing and maintaining pathophysiological processes such as neuroinflammation, excitotoxixity, oxidative stress, tau hyperphosphorilation and A aggregation (Morrison and Lyketsos, 2005; Dyrks et al., 1992). The generation of A from Amyloid-Precursor-Protein (APP) is a complex pathway and involving enzymatic cleavage of transmembrane APP protein. This may result in amyloid accumulation secondary to an imbalance between protein fragment production and its clearance (Schaeffer et al., 2011; Philipson et al., 2010; Hardy and Higgins, 1992; Estus et al., 1997; Cummings, 2004; Morrison and Lyketsos, 2005). Besides its well known pathophysiological role by various neurodegenerative diseases, earlier studies further demonstrated that free radical production is also involved in the generation of A aggregation (Dyrks et al., 1992; Hensley et al., 1994) suggesting a potential inhibiting role of radical scavengers on A related neurotoxicity. Tomiyama et al. reported that rifampicin inhibited aggregation and fibril formation of synthetic A 1–40 peptide and related neurotoxicity in a dose-dependent manner on rat pheochromocytoma PC12 cells (Tomiyama et al., 1994, 1996b). This suggested that at least one mechanism of rifampicin-mediated inhibition of A aggregation may include scavenging of free radicals and supported a potential therapeutic role of rifampicin for Alzheimer’s disease. Rifampicin may exert its neuroprotective effects in addition to scavenging free radicals by inhibition of amyloid fibril formation (Tomiyama et al., 1997). In accordance with these studies recent evidence strongly suggests that impaired clearance of A across the BBB might lead to the formation of A brain deposits and Alzheimer’s disease progression (Endoh et al., 1999; Cirrito et al., 2005; Vogelgesang et al., 2002; Kuhnke et al., 2007; Lam et al., 2001). Thus, the efflux transporter permeability glycoprotein (P-gp) may play an important role for the elimination of A1–40 and A1–42 from the brain across the BBB (Endoh et al., 1999; Cirrito et al., 2005; Vogelgesang et al., 2002; Kuhnke et al., 2007; Lam et al., 2001). Abuznait et al. demonstrated that decreased intracellular accumulation of A1–40 is associated with P-gp up-regulation caused by rifampicin (Lam et al., 2001). These findings were consistent with their results on an in vitro concentration-dependent increase in Pgp expression and activity by various drugs, including rifampicin (Abuznait et al., 2011a). Moreover, a very recent mice study has shown that the upregulation of Low density lipoprotein receptorrelated protein 1 (LRP1) and P-gp at the BBB by rifampicin and caffeine enhanced brain A clearance and suggested the presence of a possible transporter/receptor that plays an important role in A clearance which is upregulated by rifampicin (Abuznait et al., 2011b). All these findings together support a possible relationship between P-gp dysregulation and cognitive improvement in
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Table 1 Summary of positive trials of rifampicin treatment for neuroprotection. Disease
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Outcome
Study
Source
Animal
Human
Stroke
↓ Infarct volumes ↓ Apoptotic cell death
+
−
Yulug et al. (2004)
Menengitis
↓ Neuronal damage ↓ Proinflamatory mediators ↓ ROS production ↓ Mortality ↑ Clinical survival
+
+
Nau et al. (1999) Böttcher et al. (2000) Stuertz et al. (1998) Schmidt et al. (1997) Trostdorf et al. (1999) Ruslami et al. (2013) Alvarez-Uria et al. (2013)
Optic nerve injury
↓ Apoptotic retinal ganglion cell death
+
−
Kilic et al. (2004)
Parkinson’s disease
↑ Dopaminergic cell survival ↓ Alpha synuclein expression ↑ GRP78 expression ↓ MPP+-induced apoptosis
+
−
Kilic et al. (2004) Oida et al. (2006) Xu et al. (2007) Li et al. (2004) Chen et al. (2010) Jing et al. (2014)
Alzheimer’s disease
↓ Amyloid Beta aggregation ↑ Amyloid Beta clearance ↑ P-gp Improved clinical SADAScog score
+
+
Tomiyama et al. (1994, 1997) Abuznait et al. (2011a) Qosa et al. (2012) Loeb et al. (2004) Namba et al. (1992)
patients with Alzheimer’s disease suggesting that in addition to oxidative injury and fibril aggregation, targeting P-gp by rifampicin could be an effective strategy in decreasing the progression of Alzheimer’s disease. In contrast to the rapidly increasing preclinical data, only a few clinical studies evaluated the effects of rifampicin in patients with Alzheimer’ disease. Namba et al. reported by their recent study that non-demented elderly leprosy patients that were on rifampicine treatment for years showed an unusual absence of senile plaques in their brains compared with age-matched controls (Namba et al., 1992). Another study by Loeb et al. showed that oral daily doses of rifampin 300 mg for 3 months in patients with
mild to moderate AD improved cognitive function measured with the Standardized Alzheimer’s Disease Assessment Scale-Cognitive Subscale (SADAScog score) (Qosa et al., 2012). However, these promising pilot results could not be replicated in a recent study were patients were treated twelve months with rifampicin (Loeb et al., 2004). Overall, despite strong preclinical evidences this controversial clinical findings together suggest that more clinical research and related functional neuroimaging data (etc. amyloidPET) with combined clinical assessment scores is needed in order to investigate the clinical relevance of the neuroprotective effect of Q4 rifampicin (Table 1 and Fig. 1).
Anti-apoptotic
Anti-inflamatory
•Stimulates anti-apoptotic Bcl-2, Bcl-XL, XIAP, CIAP2 and FLIP activities
•Reduces pro-inflamatory cytokines and bacterial compounds
•Reduces pro-apoptotic Bax, Caspase 3 and caspase 8 activities
•Reduces NF B, MAPKs and TLR-2 activities •Increases GR agonist activity
•Increases eNOS activity
Rifampicin
Anti-oxidant
Anti-Alzheimer
•Reduces ROS production
•Reduces A β aggregation
•Reduces mitochondrial oxidative stress
•Reduces amyloid fibril formation •Increases permeability glycoprotein
Anti-Parkinson •Reduces MPP + toxicity •Reduces alpha-synuclein aggregation •Increases glucose-regulated protein 78 Fig. 1. Multiple mechanisms of rifampicin.
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Besides studies suggesting free radical scavenging as a potential neuroprotective mechanism of rifampicin, earlier studies have further shown that rifampicin can also activate glucocorticoid receptors (Calleja et al., 1998). Despite conflicting reports regarding the protective role of corticosteroids (Wallerath et al., 1999), the activation of glucocorticoid receptors has been shown not only to mediate neuroprotection but also exert to myocardioprotective effects mediated by nontranscriptional activation of endothelial nitric oxide synthase (eNOS) through the PI3K/Akt pathway (Hafezi-Moghadam et al., 2002). Additionally, high-dose corticosteroids given within 2 h of transient cerebral ischemia were shown to increase eNOS activity, augment regional cerebral blood flow and reduce cerebral infarct size abolished by treatment with the glucocorticoid receptor (GR) antagonist (Limbourg et al., 2002). This was suggested by Gollapudi et al. (2003) who reported rifampicinmediated inhibition of peripheral blood T lymphocyte apoptosis via GR activation which was associated by inhibition of activation of both caspase-3 and caspase-8 and reversed by GR antagonist (RU486). However rifampicin’s agonist activity on the glucocorticoid receptor may function also as an immunodepressor that can help to decrease host related neuronal damage by neuroinflamation (Calleja et al., 1998; Nau et al., 1999). Additionally, recent studies showed that rifampicin may lead to induction of gene transcription controlled by glucocorticoid receptor- binding elements (Calleja et al., 1998) which were shown to exist in isolated Müller and photoreceptor cells in intact salamander retina and in all cell types in the human eye (Psarra et al., 2003). Activated GRs can inhibit activator protein (AP-1), which is essential for the induction of photoreceptor apoptosis by light and GR-mediated inhibition may occur in the nucleus of retinal cells by a protein- protein interaction of both transcription factors. Thus, induction of GR activity has been shown to prevent light-induced retinal degeneration by interference with AP-1-dependent steps of apoptosis induction in mice (Wenzel et al., 2001). Furthermore regarding recent hypothesis suggesting the role of neuroinflamation related glucocorticoid receptor-signaling insufficiency in the development of Alzheimer’s disease, rifampicin may play an important role in the progress of the disease via the activation of glucocorticoid receptors (Alvarez-Uria et al., 2013).
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2. Conclusion
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The antibiotic rifampicin exerts strong brain protective in various in vivo and in vitro models of neurodegenerative disease including Stroke, Parkinson’s, Alzheimer’s. Pilot clinical studies suggest that patients with neurodegenerative diseases may benefit from rifampicin treatment. These promising findings should be further explored in larger preclinical therapeutic studies and further on in randomized early phase clinical trials. Uncited reference Yerramasetti et al. (2002). References Abuznait, A.H., Cain, C., Ingram, D., Burk, D., Kaddoumi, A., 2011a. Up-regulation of Pglycoprotein reduces intracellular accumulation of beta amyloid: investigation of P-glycoprotein as a novel therapeutic target for Alzheimer’s disease. J. Pharm. Pharmacol. 63, 1111–1118. Abuznait, A.H., Patrick, S.G., Kaddoumi, A., 2011b. Exposure of LS-180 cells to drugs of diverse physicochemical and therapeutic properties up-regulates Pglycoprotein expression and activity. J. Pharm. Pharm. Sci. 14, 236–248. Acocella, G., 1978. Clinical pharmacokinetics of rifampicin. Clin. Pharmacokinet. 3, 108–127.
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