J Acupunct Meridian Stud 2014;7(4):173e179
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Cholinergic Vasodilative System in the Cerebral Cortex: Effects of Acupuncture and Aging Sae Uchida* Department of Autonomic Neuroscience, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan Available online 23 June 2014
Received: Feb 20, 2014 Accepted: Feb 25, 2014 KEYWORDS acupuncture; aging; cerebral blood flow; cholinergic vasodilation; moxibustion; nucleus basalis of Meynert
Abstract This article presents a review of our studies on the cholinergic vasodilative system in the cerebral cortex in relation to the effects of acupuncture and aging. In anesthetized rats, manual acupuncture-like stimulation of the cheek, forepaw, upper arm, and hindpaw increases the cortical cerebral blood flow (CBF). The mechanism for the increased response of CBF due to forepaw stimulation has been found to be a reflex response whose afferents are Groups III and IV somatic afferent fibers and whose efferents are cholinergic fibers that originate in the nucleus basalis of Meynert. Although the cholinergic cortical vasodilation to nucleus basalis of Meynert stimulation at high intensities declines with age, the increased response of CBF induced by natural somatic afferent stimulation, such as an acupuncture-like stimulation of a forepaw, is well maintained even in very old rats (approximately 3 years of age). These findings in anesthetized rats may support the application of acupuncture to elderly people and patients with disturbances in the CBF by activating the intracranial cholinergic vasodilative system.
1. Introduction Disturbances in the cerebral blood flow (CBF) may impair consciousness and motor and visceral functions. Acupuncture has been used to improve the dysfunctions caused by
disturbances in the CBF, such as stroke [1,2], but the mechanisms of this improvement have not yet been clarified. A cholinergic neural vasodilative response in the cortex, independent of systemic blood pressure and metabolic
* Corresponding author. Department of Autonomic Neuroscience, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaecho, Itabashi-ku, Tokyo 173-0015, Japan. E-mail: [email protected] (S. Uchida). pISSN 2005-2901 eISSN 2093-8152 http://dx.doi.org/10.1016/j.jams.2014.02.006 Copyright ª 2014, International Pharmacopuncture Institute.
174 vasodilation, has been reported to occur when cholinergic neurons originating in the magnocellular nucleus of the basal forebrain (the nucleus basalis of Meynert; NBM) and projecting to the cortex are activated [3,4]. This cholinergic vasodilative system, which operates by increasing acetylcholine (ACh) release, relies upon the activation of both muscarinic and nicotinic ACh receptors in the parenchyma of the cortex [3,5]. Cutaneous mechanical sensory stimulation, such as pinching of the skin, has been shown to excite NBM cholinergic neurons [6], release ACh in the cortex [7], and consequently increase the cortical CBF [8]. These results indicate that insufficient cerebral circulation is improved by the stimulation of the skin and underlying muscles through acupuncture. The cholinergic neurons in the basal forebrain show degeneration in patients with Alzheimer’s disease and in healthy aged people [9e11]. It is very important to determine whether the cholinergic vasodilator effect of NBM on the cortical CBF changes with age. First, this study reviews animal studies that examined the effect of acupuncture-like stimulation on the cortical CBF with regard to the intracranial cholinergic vasodilative system [12]. Second, it reviews studies on aging of the intracranial cholinergic vasodilative system [13e15]. Finally, the effects of acupuncture-like stimulation on the cortical CBF examined in aged rats are presented. The effect of moxibustion-like stimulation on the cortical CBF is also tested and discussed here [16].
2. CBF responses in the parietal cortex to acupuncture-like stimulation to various areas Acupuncture-like manual stimulation delivered to various segmental areas produced various responses for the cortical CBF in both the parietal cortex and the mean arterial pressure (MAP). Stimulation of the cheek, forepaw, upper arm, and hindpaw produced significant increases in the CBF, but that of the chest, back, lower leg, and perineum did not produce significant responses (Fig. 1A and C). The CBF responses were presented in both sides, ipsilateral and contralateral to the site stimulated. Both ipsilateral and contralateral CBF responses were almost identical, and no significant differences were found (Fig. 1C). Stimulation of the cheek, forepaw, and hindpaw produced an increase in the MAP, whereas that of the back produced a decrease in the MAP. Stimulation of the upper arm, chest, lower leg, and perineum did not produce a significant response in the MAP. Although there were slight discrepancies between the responses of the CBF and the MAP, as stated above, there was a general tendency to produce both these responses in parallel.
3. Neural mechanism of CBF response produced by acupuncture-like stimulation To prevent an increase in the MAP following an acupuncture-like stimulation of a forepaw, the spinal cord was transected at the first to second thoracic level (T1e2). After the spinal transection, sensory information from the forepaw could ascend via the normal circuitry to the brain
S. Uchida through the cervical spinal cord, propagate to the cardiovascular center in the brainstem, and be integrated into the brainstem; however, the information integrated into the brainstem could not descend to the preganglionic sympathetic neurons in the thoracic and lumbar spinal cord because of the transection of the descending pathways at the top of the T1e2 level of the spinal cord. After spinal transection at T1e2 level, manual acupuncture-like stimulation to the forepaw for 1 minute no longer produced MAP responses, but still produced the increased CBF responses (Fig. 1B and D). This result indicates that the CBF response is independent of MAP. Both ipsilateral and contralateral CBF responses were almost identical; no significant differences were found. In the spinalized condition, moxibustion-like stimulation, performed by burning an approximately 4 mg moxa cone placed on the forepaw skin, produced a significant increase in the CBF both ipsilateral and contralateral to the site of stimulation [16]. The increased CBF following either acupuncture- or moxibustion-like stimulation to a forepaw was completely abolished after severing the brachial plexus, indicating the inevitable role of somatic afferents in the CBF responses produced by acupuncture- and moxibustion-like stimulation. Acupuncture-like manual stimulation for 1 minute delivered to a forepaw between the second and third digits excited ipsilateral radial, ulnar, and median afferent nerves, innervating the stimulation area. To define the fiber groups, an electrical current was passed through two acupuncture needles inserted into a forepaw. The CBF was increased by repetitive electrical stimulation (electroacupuncture stimulation) only when the stimulus intensity was above the threshold of Group III nerve fibers. Stimulation with supramaximal intensity for all group fibers, including Group IV fibers, produced an even larger increase in the CBF. These results indicate that Groups III and IV afferents are responsible for the CBF response induced by acupuncture-like stimulation. The CBF response elicited by electroacupuncture stimulation of a forepaw in the spinalized rats did not change significantly by bilaterally cutting either the sympathetic nerves innervating the cerebral blood vessels at the cervical level or the parasympathetic nerves innervating cerebral blood vessels at the palatine ganglia of the facial nerves for parasympathetic nerves. These results indicate that sympathetic and parasympathetic efferents are not essential to the CBF response. The CBF responses were attenuated after an intravenous (i.v.) injection of atropine, a bloodebrain barrier (BBB)permeable muscarinic ACh receptor antagonist, and were further attenuated by an additional i.v. injection of mecamylamine, a BBB-permeable nicotinic ACh receptor blocker (Fig. 2). By contrast, the CBF responses were not affected significantly by i.v. injections of BBB-impermeable muscarinic and nicotinic ACh receptor antagonists. The CBF response produced by moxibustion-like stimulation of a forepaw was also attenuated by BBB-permeable blockers, atropine, and mecamylamine. These results suggest that activations of both muscarinic and nicotinic ACh receptors in the parenchyma are important to produce CBF response by acupuncture- and moxibustion-like stimulation. Activation of both muscarinic and nicotinic ACh receptors in the
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Figure 1 Effect of manual acupuncture-like stimulation of various areas on the CBF in the parietal cortex and MAP. Sample recordings of the CBF in the parietal cortex ipsilateral to the stimulating site and the MAP following acupuncture-like stimulation of a forepaw for 1 minute (indicated by horizontal bars) in (A) CNS-intact and (B) spinalized rats. (C, D) Summary of CBF responses (white column: ipsilateral to the stimulated site; hatched column: contralateral to the stimulated site) and the MAP. Each point and each vertical bar represent a mean SEM. Note. From “Effect of acupuncture-like stimulation on cortical cerebral blood flow in anesthetized rats,” by S. Uchida, F. Kagitani, A. Suzuki, and Y. Aikawa, 2000, Jpn J Physiol, 50, p. 495e507. Copyright 2000, The physiological Society of Japan. Adapted with permission. )p < 0.05; significantly different from prestimulus control values using a paired t test. yp < 0.01; significantly different from prestimulus control values using a paired t test. A Z upper arm; B Z back; C Z chest; CBF Z cerebral blood flow; CK Z cheek; CNS Z central nervous system; FP Z forepaw; HP Z hindpaw; L Z lower leg; MAP Z mean arterial pressure; P Z perineum; SEM Z standard error of the mean.
parenchyma of the cortex is involved in NBM cholinergic vasodilation in the cerebral cortex [3]. The CBF response elicited by the electroacupuncture stimulation of a forepaw in the spinalized rats was completely abolished by lesioning the bilateral NBM (Fig. 3). This evidence may suggest the activation of an intrinsic cholinergic vasodilative system originating in the NBM by acupuncture- and moxibustion-like stimulation. Extracellular ACh in the parietal cortex was increased following acupuncture-like manual stimulation of the forepaw (Fig. 4). This ACh appeared to be released from the cholinergic nerve terminals in the cortex following acupuncture-like stimulation. Akaishi et al [6] demonstrated the excitation of NBM neurons by cutaneous
pinching in anesthetized rats, and Biesold et al [3] demonstrated that the increase in CBF was induced by exciting the NBM cholinergic vasodilative system. Therefore, the activation of the intracranial cholinergic system originating in the NBM is important for eliciting an increase in the CBF following acupuncture- and moxibustion-like stimulation. The CBF responses elicited by both the electroacupuncture and the moxibustion stimulation of a forepaw in the spinalized rats were not influenced by an i.v. injection of naloxone, an opioid receptor antagonist, indicating that the endogenous opioid system is not directly involved in the present CBF response elicited by acupuncture- and moxibustion-like stimulation [12,16].
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Figure 2 Effect of cholinergic receptor antagonists permeable to the BBB on CBF responses induced by EAS of a forepaw in spinalized rats. (AeC) Sample recordings of the CBF. (D) Summary of CBF responses. Note. From “Effect of acupuncture-like stimulation on cortical cerebral blood flow in anesthetized rats,” by S. Uchida, F. Kagitani, A. Suzuki, and Y. Aikawa, 2000, Jpn J Physiol, 50, p. 495e507. Copyright 2000, The Physiological Society of Japan. Adapted with permission. )p < 0.05; significant difference between the responses by Student t test. yp < 0.01; significant difference between the responses by Student t test. ATR Z atropine; BBB Z bloodebrain barrier; CBF Z cerebral blood flow; EAS Z electroacupuncture stimulation; MEC Z mecamylamine.
We can summarize that the CBF response elicited by the acupuncture- and moxibustion-like stimulation of a forepaw in rats, independent of the MAP, is a reflex response whose afferents are somatic afferent fibers (Groups III and
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Figure 3 Effect of bilateral destruction of the NBM and substantia innominata on the responses of the CBF to EAS of a forepaw in spinalized rats. (A, B) Sample recordings of the CBF. (C) Summary of CBF responses. Note. From “Effect of acupuncture-like stimulation on cortical cerebral blood flow in anesthetized rats,” by S. Uchida, F. Kagitani, A. Suzuki, and Y. Aikawa, 2000, Jpn J Physiol, 50, p. 495e507. Copyright 2000, The Physiological Society of Japan. Adapted with permission. )p < 0.05; significant difference between the responses by Student t test. CBF Z cerebral blood flow; EAS Z electroacupuncture stimulation; NBM Z nucleus basalis of Meynert.
IV fibers in the case of acupuncture) and efferents are cholinergic fibers originating in the NBM (Fig. 5).
4. Age-related changes in the cholinergic vasodilative system originating in the NBM and projecting to the cerebral cortex The cholinergic vasodilative function in the cerebral cortex elicited by stimulation of the NBM was determined in three different age cohorts of rats: young adult (4e7 months), old (24e25 months), and very old (32e42 months). Responses of the parietal or frontal CBF tested at three different intensities (50 mA, 100 mA, and 200 mA) were well maintained in old rats compared with young adult rats. In very old rats, the response at 50 mA was not significantly different from that in young adult and old rats, but the responses at 100 mA and 200 mA were significantly attenuated (Fig. 6). Nonetheless, basal extracellular ACh release in the parietal or frontal cortex of young adult, old, and very old rats was not significantly different. The response of the extracellular ACh release to NBM stimulation was dependent on the stimulus intensity. The responses of ACh tested at 50 mA, 100 mA, and 200 mA intensities did not differ significantly in these three different age groups. Age-related changes in the CBF response mediated by nicotinic ACh receptors were examined using an i.v. injection of nicotine and by measuring the cortical CBF in rats of the three different age cohorts. Nicotine (3e30 mg/kg) increased the cortical CBF in a dose-dependent manner (Fig. 7A and D). Blood pressure was not influenced at 0.3e30 mg/kg nicotine. The threshold dose of nicotine for
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Figure 4 Effects of manual acupuncture-like stimulation of the forepaw on the extracellular ACh release in the parietal cortex ipsilateral (white column) or contralateral (hatched column) to the stimulation site in CNS-intact rats. Each column and each vertical bar shows mean SEM. Note. From “Effect of acupuncture-like stimulation on cortical cerebral blood flow in anesthetized rats,” by S. Uchida, F. Kagitani, A. Suzuki, and Y. Aikawa, 2000, Jpn J Physiol, 50, p. 495e507. Copyright 2000, The Physiological Society of Japan. Adapted with permission. )p < 0.01; significantly different from the prestimulus control value using a one-way repeated ANOVA followed by Dunnett’s multiple comparison test. ACh Z acetylcholine; ANOVA Z analysis of variance; CNS Z central nervous system; SEM Z standard error of the mean.
increasing the CBF shifted from 3 mg/kg in young adult rats (3e10 months) to 30 mg/kg in old rats (23e26 months) (Fig. 7B and D), and the nicotine-induced increase in the CBF was considerably reduced in very old rats (32e36 months) (Fig. 7C and D). In very old rats, the 30 mg/kg dose of nicotine did not have any effect on the CBF. Involvement of muscarinic ACh receptors in the cholinergic vasodilator response in the cortex elicited by stimulation with the agonist arecoline was also examined in rats of three different age cohorts. Rats were pretreated with methylatropine (a BBB-impermeable muscarinic ACh receptor antagonist), and the spinal cord was transected at the first cervical level to prevent any changes in the blood pressure by arecoline. There were dose-dependent responses in the CBF to i.v. injections of arecoline under these
cerebral blood flow vasodilatation mAChR cerebral cortex
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specific conditions in young adult, old, and very old rats. The thresholds of doses were between 20 mg/kg and 60 mg/kg, and the magnitudes of the arecoline-induced responses of the CBF tested at doses of 60 mg/kg, 200 mg/kg, and 600 mg/kg were not significantly different between the three groups, indicating that the muscarinic ACh receptor activity was well maintained during aging. From these results, it can be concluded that the decrease in NBM stimulation-induced vasodilatation in very old rats is due to a decrease in nicotinic ACh receptor function. This conclusion is consistent with the findings of Nordberg et al [17], who observed that human cortical nicotinic ACh receptors declined more than muscarinic ACh receptors during aging. Of the several subtypes of nicotinic ACh receptors, the a4b2 and a7 subtypes are most abundant and widespread in the mammalian brain, including the cerebral cortex [18,19]. The nicotine-induced increase in the CBF is found to be mediated by a4b2-like nicotinic ACh receptors and not by a7 nicotinic ACh receptors [15]. Impairment of the cholinergic neural regulation of cortical CBF via the activation of a4b2-like nicotinic ACh receptors may cause the deterioration of cognitive function in old age or in pathological conditions such as Alzheimer’s disease.
5. Cortical CBF responses in the parietal cortex to acupuncture-like stimulation in very old rats
NBM acupuncture, moxibustion
Figure 5 Schematic diagram of a possible mechanism of cerebral vasodilation produced by acupuncture and moxibustion stimulation of a forepaw. ACh Z acetylcholine; mAChR Z muscarinic ACh receptor; nAChR Z nicotinic ACh receptor; NBM Z nucleus basalis of Meynert.
In very old rats (approximately 3 years old), the effect of manual acupuncture-like stimulation of a forepaw on the cortical CBF was investigated and compared with similar responses in young adult rats. In very old rats whose spinal cord was transected at the T1e2 level, acupuncture-like stimulation of a forepaw produced an increase in the CBF in the parietal cortex. The magnitude of increase in the CBF by
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Figure 6 Responses of the CBF in the parietal cortex to unilateral focal electrical stimulation of the ipsilateral NBM in (A, D) young adult, (B, D) old, and (C, D) very old rats. (AeC) Sample recordings of CBF response to electrical stimulation of the NBM with parameters of 200 mA, 0.5 milliseconds, 50 Hz, for 1.5 minutes (indicated by the black bars). (D) Graphs of relationships between the stimulus intensity (abscissa) and the magnitude of increase in the CBF (ordinate). The magnitudes of the responses during the stimulus period are expressed as percentages of the prestimulus control values for 1.5 minutes just prior to stimulation. Each point and each vertical bar show mean SEM. Note. From “Effects of age on cholinergic vasodilation of cortical cerebral blood vessels in rats,” by S. Uchida, A. Suzuki, F. Kagitani, and H. Hotta, 2000, Neurosci Lett, 294, p. 109e12. Copyright 2000, Elsevier Science Ireland Ltd. Adapted with permission. )p < 0.05; significantly different from the values of young adult rats using the KruskaleWallis test followed by Dunn’s test. CBF Z cerebral blood flow; NBM Z nucleus basalis of Meynert; SEM Z standard error of the mean.
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Figure 7 Responses of the CBF in the frontal cortex to i.v. injections of nicotine in (A, D) young adult, (B, D) old, and (C, D) very old rats. (AeC) Sample recordings of the CBF and the MAP to i.v. injections of nicotine (30 mg/kg). Note. From “Effect of stimulation of nicotinic cholinergic receptors on cortical cerebral blood flow and changes in the effect during aging in anesthetized rats,” by S. Uchida, F. Kagitani, H. Nakayama, and A. Sato, 1997, Neurosci Lett, 228, p. 203e6. Copyright 1997, Elsevier Science Ireland Ltd. Adapted with permission. )p < 0.05; significantly different from preinjection control values. ))p < 0.01; significantly different from preinjection control values. CBF Z cerebral blood flow; i.v. Z intravenous; MAP Z mean arterial pressure.
Acupuncture-induced cerebral vasodilation and aging acupuncture-like stimulation in very old rats was not significantly different from that in young adult rats (Uchida et al, unpublished observations). These results suggest that the NBM cholinergic vasodilative system functions well even in very old rats when activated by acupuncture-like stimulation.
6. Conclusion After emotional factors are eliminated by means of anesthesia, either acupuncture- or moxibustion-like stimulation, applied to the cheeks and limbs (especially forepaw and hindpaw) of rats, increases the cortical CBF. The increase in the CBF elicited by the stimulation of a forepaw was proved to be a reflex response. Its afferent pathway consists of somatic afferent nerves; the impulses that are generated activate the intracranial cholinergic vasodilative system, eventually increasing the CBF in the cortex. Although the cholinergic cortical vasodilation response to NBM stimulation at high intensities declines with age, the increased responses of CBF elicited by natural somatic afferent stimulation, such as acupuncture-like stimulation, occur even in very old rats (approximately 3 years of age). Disturbances in the CBF, such as stroke, may impair consciousness and motor and visceral functions. Furthermore, regional CBF is known to correlate with cognitive function in both healthy young and healthy old people, as well as in patients with Alzheimer’s disease [20,21]. The loss of cholinergic neurons in the basal forebrain [22] and nicotinic ACh receptors in the cerebral cortex [23,24] is known to correlate with cognitive impairment in patients with Alzheimer’s disease. Our experimental findings in healthy but anesthetized rats may support the application of acupuncture and moxibustion in elderly people and in patients with disturbances in the CBF, for example, stroke [1,2], and Alzheimer’s disease [25], because it is able to activate the basal forebrain cholinergic vasodilative system and consequently increase the CBF.
Disclosure statement The author affirms there are no conflicts of interest and the author has no financial interest related to the material of this manuscript.
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179 [6] Akaishi T, Kimura A, Sato A, Suzuki A. Responses of neurons in the nucleus basalis of Meynert to various afferent stimuli in rats. NeuroReport. 1990;1:37e39. [7] Kurosawa M, Sato A, Sato Y. Cutaneous mechanical sensory stimulation increases extracellular acetylcholine release in cerebral cortex in anesthetized rats. Neurochem Int. 1992;21: 423e427. [8] Adachi T, Meguro K, Sato A, Sato Y. Cutaneous stimulation regulates blood flow in cerebral cortex in anesthetized rats. NeuroReport. 1990;1:41e44. [9] Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, DeLong MR. Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain. Science. 1982;215:1237e1239. [10] McGeer PL, McGeer EG, Suzuki J, Dolman CE, Nagai T. Aging, Alzheimer’s disease, and the cholinergic system of the basal forebrain. Neurology. 1984;34:741e745. [11] Grothe M, Heinsen H, Teipel S. Longitudinal measures of cholinergic forebrain atrophy in the transition from healthy aging to Alzheimer’s disease. Neurobiol Aging. 2013;34:1210e1220. [12] Uchida S, Kagitani F, Suzuki A, Aikawa Y. Effect of acupuncture-like stimulation on cortical cerebral blood flow in anesthetized rats. Jpn J Physiol. 2000;50:495e507. [13] Uchida S, Kagitani F, Nakayama H, Sato A. Effect of stimulation of nicotinic cholinergic receptors on cortical cerebral blood flow and changes in the effect during aging in anesthetized rats. Neurosci Lett. 1997;228:203e206. [14] Uchida S, Suzuki A, Kagitani F, Hotta H. Effects of age on cholinergic vasodilation of cortical cerebral blood vessels in rats. Neurosci Lett. 2000;294:109e112. [15] Uchida S, Hotta H, Kawashima K. Long-term nicotine treatment reduces cerebral cortical vasodilation mediated by alpha4beta2-like nicotinic acetylcholine receptors in rats. Eur J Pharmacol. 2009;609:100e104. [16] Uchida S, Suzuki A, Kagitani F, Nakajima K, Aikawa Y. Effect of moxibustion stimulation of various skin areas on cortical cerebral blood flow in anesthetized rats. Am J Chin Med. 2003; 31:611e621. [17] Nordberg A, Alafuzoff I, Winblad B. Nicotinic and muscarinic subtypes in the human brain: changes with aging and dementia. J Neurosci Res. 1992;31:103e111. [18] Picciotto MR, Caldarone BJ, Brunzell DH, Zachariou V, Stevens TR, King SL. Neuronal nicotinic acetylcholine receptor subunit knockout mice: physiological and behavioral phenotypes and possible clinical implications. Pharmacol Ther. 2001;92:89e108. [19] Gaimarri A, Moretti M, Riganti L, Zanardi A, Clementi F, Gotti C. Regulation of neuronal nicotinic receptor traffic and expression. Brain Res Rev. 2007;55:134e143. [20] Ushijima Y, Okuyama C, Mori S, Nakamura T, Kubota T, Nishimura T. Relationship between cognitive function and regional cerebral blood flow in Alzheimer’s disease. Nucl Med Commun. 2002;23:779e784. [21] Bertsch K, Hagemann D, Hermes M, Walter C, Khan R, Naumann E. Resting cerebral blood flow, attention, and aging. Brain Res. 2009;1267:77e88. [22] Schliebs R, Arendt T. The significance of the cholinergic system in the brain during aging and in Alzheimer’s disease. J Neural Transm. 2006;113:1625e1644. [23] Kadir A, Almkvist O, Wall A, La ˚ngstro ¨m B, Nordberg A. PET imaging of cortical 11C-nicotine binding correlates with the cognitive function of attention in Alzheimer’s disease. Psychopharmacology (Berl). 2006;188:509e520. [24] Sabri O, Kendziorra K, Wolf H, Gertz HJ, Brust P. Acetylcholine receptors in dementia and mild cognitive impairment. Eur J Nucl Med Mol Imaging. 2008;35(Suppl. 1):S30e45. [25] Zeng BY, Salvage S, Jenner P. Effect and mechanism of acupuncture on Alzheimer’s disease. Int Rev Neurobiol. 2013; 111:181e195.
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Cholinergic Vasodilative System in the Cerebral Cortex: Effects of Acupuncture and Aging Sae Uchida* Department of Autonomic Neuroscience, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan Available online 23 June 2014
Received: Feb 20, 2014 Accepted: Feb 25, 2014 KEYWORDS acupuncture; aging; cerebral blood flow; cholinergic vasodilation; moxibustion; nucleus basalis of Meynert
Abstract This article presents a review of our studies on the cholinergic vasodilative system in the cerebral cortex in relation to the effects of acupuncture and aging. In anesthetized rats, manual acupuncture-like stimulation of the cheek, forepaw, upper arm, and hindpaw increases the cortical cerebral blood flow (CBF). The mechanism for the increased response of CBF due to forepaw stimulation has been found to be a reflex response whose afferents are Groups III and IV somatic afferent fibers and whose efferents are cholinergic fibers that originate in the nucleus basalis of Meynert. Although the cholinergic cortical vasodilation to nucleus basalis of Meynert stimulation at high intensities declines with age, the increased response of CBF induced by natural somatic afferent stimulation, such as an acupuncture-like stimulation of a forepaw, is well maintained even in very old rats (approximately 3 years of age). These findings in anesthetized rats may support the application of acupuncture to elderly people and patients with disturbances in the CBF by activating the intracranial cholinergic vasodilative system.
1. Introduction Disturbances in the cerebral blood flow (CBF) may impair consciousness and motor and visceral functions. Acupuncture has been used to improve the dysfunctions caused by
disturbances in the CBF, such as stroke [1,2], but the mechanisms of this improvement have not yet been clarified. A cholinergic neural vasodilative response in the cortex, independent of systemic blood pressure and metabolic
* Corresponding author. Department of Autonomic Neuroscience, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaecho, Itabashi-ku, Tokyo 173-0015, Japan. E-mail: [email protected] (S. Uchida). pISSN 2005-2901 eISSN 2093-8152 http://dx.doi.org/10.1016/j.jams.2014.02.006 Copyright ª 2014, International Pharmacopuncture Institute.
174 vasodilation, has been reported to occur when cholinergic neurons originating in the magnocellular nucleus of the basal forebrain (the nucleus basalis of Meynert; NBM) and projecting to the cortex are activated [3,4]. This cholinergic vasodilative system, which operates by increasing acetylcholine (ACh) release, relies upon the activation of both muscarinic and nicotinic ACh receptors in the parenchyma of the cortex [3,5]. Cutaneous mechanical sensory stimulation, such as pinching of the skin, has been shown to excite NBM cholinergic neurons [6], release ACh in the cortex [7], and consequently increase the cortical CBF [8]. These results indicate that insufficient cerebral circulation is improved by the stimulation of the skin and underlying muscles through acupuncture. The cholinergic neurons in the basal forebrain show degeneration in patients with Alzheimer’s disease and in healthy aged people [9e11]. It is very important to determine whether the cholinergic vasodilator effect of NBM on the cortical CBF changes with age. First, this study reviews animal studies that examined the effect of acupuncture-like stimulation on the cortical CBF with regard to the intracranial cholinergic vasodilative system [12]. Second, it reviews studies on aging of the intracranial cholinergic vasodilative system [13e15]. Finally, the effects of acupuncture-like stimulation on the cortical CBF examined in aged rats are presented. The effect of moxibustion-like stimulation on the cortical CBF is also tested and discussed here [16].
2. CBF responses in the parietal cortex to acupuncture-like stimulation to various areas Acupuncture-like manual stimulation delivered to various segmental areas produced various responses for the cortical CBF in both the parietal cortex and the mean arterial pressure (MAP). Stimulation of the cheek, forepaw, upper arm, and hindpaw produced significant increases in the CBF, but that of the chest, back, lower leg, and perineum did not produce significant responses (Fig. 1A and C). The CBF responses were presented in both sides, ipsilateral and contralateral to the site stimulated. Both ipsilateral and contralateral CBF responses were almost identical, and no significant differences were found (Fig. 1C). Stimulation of the cheek, forepaw, and hindpaw produced an increase in the MAP, whereas that of the back produced a decrease in the MAP. Stimulation of the upper arm, chest, lower leg, and perineum did not produce a significant response in the MAP. Although there were slight discrepancies between the responses of the CBF and the MAP, as stated above, there was a general tendency to produce both these responses in parallel.
3. Neural mechanism of CBF response produced by acupuncture-like stimulation To prevent an increase in the MAP following an acupuncture-like stimulation of a forepaw, the spinal cord was transected at the first to second thoracic level (T1e2). After the spinal transection, sensory information from the forepaw could ascend via the normal circuitry to the brain
S. Uchida through the cervical spinal cord, propagate to the cardiovascular center in the brainstem, and be integrated into the brainstem; however, the information integrated into the brainstem could not descend to the preganglionic sympathetic neurons in the thoracic and lumbar spinal cord because of the transection of the descending pathways at the top of the T1e2 level of the spinal cord. After spinal transection at T1e2 level, manual acupuncture-like stimulation to the forepaw for 1 minute no longer produced MAP responses, but still produced the increased CBF responses (Fig. 1B and D). This result indicates that the CBF response is independent of MAP. Both ipsilateral and contralateral CBF responses were almost identical; no significant differences were found. In the spinalized condition, moxibustion-like stimulation, performed by burning an approximately 4 mg moxa cone placed on the forepaw skin, produced a significant increase in the CBF both ipsilateral and contralateral to the site of stimulation [16]. The increased CBF following either acupuncture- or moxibustion-like stimulation to a forepaw was completely abolished after severing the brachial plexus, indicating the inevitable role of somatic afferents in the CBF responses produced by acupuncture- and moxibustion-like stimulation. Acupuncture-like manual stimulation for 1 minute delivered to a forepaw between the second and third digits excited ipsilateral radial, ulnar, and median afferent nerves, innervating the stimulation area. To define the fiber groups, an electrical current was passed through two acupuncture needles inserted into a forepaw. The CBF was increased by repetitive electrical stimulation (electroacupuncture stimulation) only when the stimulus intensity was above the threshold of Group III nerve fibers. Stimulation with supramaximal intensity for all group fibers, including Group IV fibers, produced an even larger increase in the CBF. These results indicate that Groups III and IV afferents are responsible for the CBF response induced by acupuncture-like stimulation. The CBF response elicited by electroacupuncture stimulation of a forepaw in the spinalized rats did not change significantly by bilaterally cutting either the sympathetic nerves innervating the cerebral blood vessels at the cervical level or the parasympathetic nerves innervating cerebral blood vessels at the palatine ganglia of the facial nerves for parasympathetic nerves. These results indicate that sympathetic and parasympathetic efferents are not essential to the CBF response. The CBF responses were attenuated after an intravenous (i.v.) injection of atropine, a bloodebrain barrier (BBB)permeable muscarinic ACh receptor antagonist, and were further attenuated by an additional i.v. injection of mecamylamine, a BBB-permeable nicotinic ACh receptor blocker (Fig. 2). By contrast, the CBF responses were not affected significantly by i.v. injections of BBB-impermeable muscarinic and nicotinic ACh receptor antagonists. The CBF response produced by moxibustion-like stimulation of a forepaw was also attenuated by BBB-permeable blockers, atropine, and mecamylamine. These results suggest that activations of both muscarinic and nicotinic ACh receptors in the parenchyma are important to produce CBF response by acupuncture- and moxibustion-like stimulation. Activation of both muscarinic and nicotinic ACh receptors in the
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Figure 1 Effect of manual acupuncture-like stimulation of various areas on the CBF in the parietal cortex and MAP. Sample recordings of the CBF in the parietal cortex ipsilateral to the stimulating site and the MAP following acupuncture-like stimulation of a forepaw for 1 minute (indicated by horizontal bars) in (A) CNS-intact and (B) spinalized rats. (C, D) Summary of CBF responses (white column: ipsilateral to the stimulated site; hatched column: contralateral to the stimulated site) and the MAP. Each point and each vertical bar represent a mean SEM. Note. From “Effect of acupuncture-like stimulation on cortical cerebral blood flow in anesthetized rats,” by S. Uchida, F. Kagitani, A. Suzuki, and Y. Aikawa, 2000, Jpn J Physiol, 50, p. 495e507. Copyright 2000, The physiological Society of Japan. Adapted with permission. )p < 0.05; significantly different from prestimulus control values using a paired t test. yp < 0.01; significantly different from prestimulus control values using a paired t test. A Z upper arm; B Z back; C Z chest; CBF Z cerebral blood flow; CK Z cheek; CNS Z central nervous system; FP Z forepaw; HP Z hindpaw; L Z lower leg; MAP Z mean arterial pressure; P Z perineum; SEM Z standard error of the mean.
parenchyma of the cortex is involved in NBM cholinergic vasodilation in the cerebral cortex [3]. The CBF response elicited by the electroacupuncture stimulation of a forepaw in the spinalized rats was completely abolished by lesioning the bilateral NBM (Fig. 3). This evidence may suggest the activation of an intrinsic cholinergic vasodilative system originating in the NBM by acupuncture- and moxibustion-like stimulation. Extracellular ACh in the parietal cortex was increased following acupuncture-like manual stimulation of the forepaw (Fig. 4). This ACh appeared to be released from the cholinergic nerve terminals in the cortex following acupuncture-like stimulation. Akaishi et al [6] demonstrated the excitation of NBM neurons by cutaneous
pinching in anesthetized rats, and Biesold et al [3] demonstrated that the increase in CBF was induced by exciting the NBM cholinergic vasodilative system. Therefore, the activation of the intracranial cholinergic system originating in the NBM is important for eliciting an increase in the CBF following acupuncture- and moxibustion-like stimulation. The CBF responses elicited by both the electroacupuncture and the moxibustion stimulation of a forepaw in the spinalized rats were not influenced by an i.v. injection of naloxone, an opioid receptor antagonist, indicating that the endogenous opioid system is not directly involved in the present CBF response elicited by acupuncture- and moxibustion-like stimulation [12,16].
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Figure 2 Effect of cholinergic receptor antagonists permeable to the BBB on CBF responses induced by EAS of a forepaw in spinalized rats. (AeC) Sample recordings of the CBF. (D) Summary of CBF responses. Note. From “Effect of acupuncture-like stimulation on cortical cerebral blood flow in anesthetized rats,” by S. Uchida, F. Kagitani, A. Suzuki, and Y. Aikawa, 2000, Jpn J Physiol, 50, p. 495e507. Copyright 2000, The Physiological Society of Japan. Adapted with permission. )p < 0.05; significant difference between the responses by Student t test. yp < 0.01; significant difference between the responses by Student t test. ATR Z atropine; BBB Z bloodebrain barrier; CBF Z cerebral blood flow; EAS Z electroacupuncture stimulation; MEC Z mecamylamine.
We can summarize that the CBF response elicited by the acupuncture- and moxibustion-like stimulation of a forepaw in rats, independent of the MAP, is a reflex response whose afferents are somatic afferent fibers (Groups III and
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Figure 3 Effect of bilateral destruction of the NBM and substantia innominata on the responses of the CBF to EAS of a forepaw in spinalized rats. (A, B) Sample recordings of the CBF. (C) Summary of CBF responses. Note. From “Effect of acupuncture-like stimulation on cortical cerebral blood flow in anesthetized rats,” by S. Uchida, F. Kagitani, A. Suzuki, and Y. Aikawa, 2000, Jpn J Physiol, 50, p. 495e507. Copyright 2000, The Physiological Society of Japan. Adapted with permission. )p < 0.05; significant difference between the responses by Student t test. CBF Z cerebral blood flow; EAS Z electroacupuncture stimulation; NBM Z nucleus basalis of Meynert.
IV fibers in the case of acupuncture) and efferents are cholinergic fibers originating in the NBM (Fig. 5).
4. Age-related changes in the cholinergic vasodilative system originating in the NBM and projecting to the cerebral cortex The cholinergic vasodilative function in the cerebral cortex elicited by stimulation of the NBM was determined in three different age cohorts of rats: young adult (4e7 months), old (24e25 months), and very old (32e42 months). Responses of the parietal or frontal CBF tested at three different intensities (50 mA, 100 mA, and 200 mA) were well maintained in old rats compared with young adult rats. In very old rats, the response at 50 mA was not significantly different from that in young adult and old rats, but the responses at 100 mA and 200 mA were significantly attenuated (Fig. 6). Nonetheless, basal extracellular ACh release in the parietal or frontal cortex of young adult, old, and very old rats was not significantly different. The response of the extracellular ACh release to NBM stimulation was dependent on the stimulus intensity. The responses of ACh tested at 50 mA, 100 mA, and 200 mA intensities did not differ significantly in these three different age groups. Age-related changes in the CBF response mediated by nicotinic ACh receptors were examined using an i.v. injection of nicotine and by measuring the cortical CBF in rats of the three different age cohorts. Nicotine (3e30 mg/kg) increased the cortical CBF in a dose-dependent manner (Fig. 7A and D). Blood pressure was not influenced at 0.3e30 mg/kg nicotine. The threshold dose of nicotine for
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Figure 4 Effects of manual acupuncture-like stimulation of the forepaw on the extracellular ACh release in the parietal cortex ipsilateral (white column) or contralateral (hatched column) to the stimulation site in CNS-intact rats. Each column and each vertical bar shows mean SEM. Note. From “Effect of acupuncture-like stimulation on cortical cerebral blood flow in anesthetized rats,” by S. Uchida, F. Kagitani, A. Suzuki, and Y. Aikawa, 2000, Jpn J Physiol, 50, p. 495e507. Copyright 2000, The Physiological Society of Japan. Adapted with permission. )p < 0.01; significantly different from the prestimulus control value using a one-way repeated ANOVA followed by Dunnett’s multiple comparison test. ACh Z acetylcholine; ANOVA Z analysis of variance; CNS Z central nervous system; SEM Z standard error of the mean.
increasing the CBF shifted from 3 mg/kg in young adult rats (3e10 months) to 30 mg/kg in old rats (23e26 months) (Fig. 7B and D), and the nicotine-induced increase in the CBF was considerably reduced in very old rats (32e36 months) (Fig. 7C and D). In very old rats, the 30 mg/kg dose of nicotine did not have any effect on the CBF. Involvement of muscarinic ACh receptors in the cholinergic vasodilator response in the cortex elicited by stimulation with the agonist arecoline was also examined in rats of three different age cohorts. Rats were pretreated with methylatropine (a BBB-impermeable muscarinic ACh receptor antagonist), and the spinal cord was transected at the first cervical level to prevent any changes in the blood pressure by arecoline. There were dose-dependent responses in the CBF to i.v. injections of arecoline under these
cerebral blood flow vasodilatation mAChR cerebral cortex
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specific conditions in young adult, old, and very old rats. The thresholds of doses were between 20 mg/kg and 60 mg/kg, and the magnitudes of the arecoline-induced responses of the CBF tested at doses of 60 mg/kg, 200 mg/kg, and 600 mg/kg were not significantly different between the three groups, indicating that the muscarinic ACh receptor activity was well maintained during aging. From these results, it can be concluded that the decrease in NBM stimulation-induced vasodilatation in very old rats is due to a decrease in nicotinic ACh receptor function. This conclusion is consistent with the findings of Nordberg et al [17], who observed that human cortical nicotinic ACh receptors declined more than muscarinic ACh receptors during aging. Of the several subtypes of nicotinic ACh receptors, the a4b2 and a7 subtypes are most abundant and widespread in the mammalian brain, including the cerebral cortex [18,19]. The nicotine-induced increase in the CBF is found to be mediated by a4b2-like nicotinic ACh receptors and not by a7 nicotinic ACh receptors [15]. Impairment of the cholinergic neural regulation of cortical CBF via the activation of a4b2-like nicotinic ACh receptors may cause the deterioration of cognitive function in old age or in pathological conditions such as Alzheimer’s disease.
5. Cortical CBF responses in the parietal cortex to acupuncture-like stimulation in very old rats
NBM acupuncture, moxibustion
Figure 5 Schematic diagram of a possible mechanism of cerebral vasodilation produced by acupuncture and moxibustion stimulation of a forepaw. ACh Z acetylcholine; mAChR Z muscarinic ACh receptor; nAChR Z nicotinic ACh receptor; NBM Z nucleus basalis of Meynert.
In very old rats (approximately 3 years old), the effect of manual acupuncture-like stimulation of a forepaw on the cortical CBF was investigated and compared with similar responses in young adult rats. In very old rats whose spinal cord was transected at the T1e2 level, acupuncture-like stimulation of a forepaw produced an increase in the CBF in the parietal cortex. The magnitude of increase in the CBF by
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Figure 6 Responses of the CBF in the parietal cortex to unilateral focal electrical stimulation of the ipsilateral NBM in (A, D) young adult, (B, D) old, and (C, D) very old rats. (AeC) Sample recordings of CBF response to electrical stimulation of the NBM with parameters of 200 mA, 0.5 milliseconds, 50 Hz, for 1.5 minutes (indicated by the black bars). (D) Graphs of relationships between the stimulus intensity (abscissa) and the magnitude of increase in the CBF (ordinate). The magnitudes of the responses during the stimulus period are expressed as percentages of the prestimulus control values for 1.5 minutes just prior to stimulation. Each point and each vertical bar show mean SEM. Note. From “Effects of age on cholinergic vasodilation of cortical cerebral blood vessels in rats,” by S. Uchida, A. Suzuki, F. Kagitani, and H. Hotta, 2000, Neurosci Lett, 294, p. 109e12. Copyright 2000, Elsevier Science Ireland Ltd. Adapted with permission. )p < 0.05; significantly different from the values of young adult rats using the KruskaleWallis test followed by Dunn’s test. CBF Z cerebral blood flow; NBM Z nucleus basalis of Meynert; SEM Z standard error of the mean.
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Figure 7 Responses of the CBF in the frontal cortex to i.v. injections of nicotine in (A, D) young adult, (B, D) old, and (C, D) very old rats. (AeC) Sample recordings of the CBF and the MAP to i.v. injections of nicotine (30 mg/kg). Note. From “Effect of stimulation of nicotinic cholinergic receptors on cortical cerebral blood flow and changes in the effect during aging in anesthetized rats,” by S. Uchida, F. Kagitani, H. Nakayama, and A. Sato, 1997, Neurosci Lett, 228, p. 203e6. Copyright 1997, Elsevier Science Ireland Ltd. Adapted with permission. )p < 0.05; significantly different from preinjection control values. ))p < 0.01; significantly different from preinjection control values. CBF Z cerebral blood flow; i.v. Z intravenous; MAP Z mean arterial pressure.
Acupuncture-induced cerebral vasodilation and aging acupuncture-like stimulation in very old rats was not significantly different from that in young adult rats (Uchida et al, unpublished observations). These results suggest that the NBM cholinergic vasodilative system functions well even in very old rats when activated by acupuncture-like stimulation.
6. Conclusion After emotional factors are eliminated by means of anesthesia, either acupuncture- or moxibustion-like stimulation, applied to the cheeks and limbs (especially forepaw and hindpaw) of rats, increases the cortical CBF. The increase in the CBF elicited by the stimulation of a forepaw was proved to be a reflex response. Its afferent pathway consists of somatic afferent nerves; the impulses that are generated activate the intracranial cholinergic vasodilative system, eventually increasing the CBF in the cortex. Although the cholinergic cortical vasodilation response to NBM stimulation at high intensities declines with age, the increased responses of CBF elicited by natural somatic afferent stimulation, such as acupuncture-like stimulation, occur even in very old rats (approximately 3 years of age). Disturbances in the CBF, such as stroke, may impair consciousness and motor and visceral functions. Furthermore, regional CBF is known to correlate with cognitive function in both healthy young and healthy old people, as well as in patients with Alzheimer’s disease [20,21]. The loss of cholinergic neurons in the basal forebrain [22] and nicotinic ACh receptors in the cerebral cortex [23,24] is known to correlate with cognitive impairment in patients with Alzheimer’s disease. Our experimental findings in healthy but anesthetized rats may support the application of acupuncture and moxibustion in elderly people and in patients with disturbances in the CBF, for example, stroke [1,2], and Alzheimer’s disease [25], because it is able to activate the basal forebrain cholinergic vasodilative system and consequently increase the CBF.
Disclosure statement The author affirms there are no conflicts of interest and the author has no financial interest related to the material of this manuscript.
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