Article in press - uncorrected proof Horm Mol Biol Clin Invest 2011;7(3):385–391 2011 by Walter de Gruyter • Berlin • Boston. DOI 10.1515/HMBCI.2011.112
Sex differences in the injured brain
Roberto Cosimo Melcangi1,* and Luis M. GarciaSegura2 1
Department of Endocrinology, Pathophysiology and Applied Biology – Center of Excellence on Neurodegenerative Diseases, Universita` degli Studi di Milano, Milano, Italy 2 Instituto Cajal, C.S.I.C., Avenida Doctor Arce 37, Madrid, Spain
Abstract Observations obtained in human and in experimental models clearly demonstrate sex differences in degenerative events occurring in the central nervous system. The present review focuses on potential factors that may contribute to these sex-dimorphic features; in particular, morphological organization of the central nervous system and functional influence by neuroactive steroids, genes, and immune system are considered.
expression of specific genes in the adult central nervous system. Sex differences in the levels of steroid hormones, neurosteroids (i.e., steroids synthesized in the nervous system), and neuroactive steroids (i.e., a definition including both steroid hormones and neurosteroids) in adulthood is the factor that has been explored in more detail, since there is solid evidence indicating that these hormones may affect the outcome of insults to the brain and the spinal cord. Finally, sex differences in the immune system have been reported. This is a critical factor for the manifestation of sex differences in autoimmune diseases and may also be relevant for other inflammatory conditions. We will briefly review here some representative examples of sex differences in brain pathology, with information obtained from clinical and animal studies. Then we will analyze the potential influence of the factors mentioned above in the generation of these differences.
Sex differences in brain pathology Keywords: gender; inflammation; neuroactive steroids; neurodegenerative diseases.
Introduction Clinical evidence and studies in animal models of central nervous system injury and neurodegeneration have revealed the existence of sex differences in the pathology of the brain and the spinal cord. These differences may be manifested in the age of onset, incidence, prevalence, or prognosis of the disease, in the tissue damage associated with the pathological condition, and/or in the response to rehabilitation or neuroprotective therapies. There are several potential factors that may contribute to generate sex differences in brain pathology. One of these factors is the existence of sex differences in the functional and morphological organization of the central nervous system. These differences are generated during the developmental period and may be the direct consequence of the expression by neural cells of specific sex differentiation genes. In addition, steroid milieu regulates the process of sex differentiation of the brain and the spinal cord. Another potential source for sex differences in brain pathology, although less explored, is the sexually dimorphic *Corresponding author: Roberto Cosimo Melcangi, Department of Endocrinology, Pathophysiology and Applied Biology – Center of Excellence on Neurodegenerative Diseases, Universita` degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy Phone: q39-02-50318238, Fax: q39-02-50318204, E-mail: [email protected] Received May 28, 2011; accepted July 6, 2011; previously published online August 15, 2011
Sex differences in the incidence and manifestation of neurodegenerative diseases
Studies in different animal models of neurodegenerative diseases have revealed the existence of sex differences in brain damage w1x. In some cases females are more affected by the pathology than males. For instance, female mice show higher seizure activity and more hippocampal neurodegeneration than male mice after the administration of kainic acid, a model of epilepsy and of excitotoxic neurodegeneration w2x. In addition, females show higher plaque load than males in different amyloid precursor protein (APP) transgenic animal models of Alzheimer’s disease w3, 4x. In transgenic mice expressing mutant APP, preselinin-1, and tau, female animals show an increased cognitive impairment w5x and an increased production and decreased degradation of b-amyloid compared to males w6x. In contrast, in a model of Parkinson’s disease in mice, caused by the intoxication with 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine, male animals show a greater depletion of dopamine than female animals w7x. Also, in transgenic animal models of Huntington’s disease, males show greater motor deficits and increased loss and atrophy of dopaminergic neurons than females w8, 9x. Sex differences in the incidence and manifestation of neurodegenerative diseases have been observed in humans w1x. The incidence of Parkinson’s disease is greater in men than in women w10–13x, and women present higher age at onset and milder motor deterioration than men w14x. Age of onset of Huntington’s disease is also higher and the course of the illness more moderate in women than in men w15–17x. In contrast, epidemiological studies support a higher prevalence
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and incidence of Alzheimer’s disease in women w18–21x. Sex differences in Alzheimer’s disease patients are also evidenced in terms of plaque load, with a significantly different distribution of them in cortical areas of female patients w22x. Women also show more neurofibrillary tangles w23x. Analysis of visuospatial episodic memory also shows sex differences, with a better performance in male than in female Alzheimer’s disease patients w24x. Clinical manifestation of dementia among Alzheimer’s disease patients is more common in women than in men w23x. As it has been reported for other autoimmune diseases w25x, the incidence of multiple sclerosis is higher in women than in men w26–28x. However, men have a worse prognosis than women w29x. Indeed, men are affected in older age and develop a more severe pathology, defined as a shorter time to reach severe disability w30x. Cognitive decline is also more predominant in men than in women w31, 32x. Sex differences in the incidence and outcome of stroke
Stroke is another pathological condition for which sex differences in the underlying etiology, presentation, and outcome have been reported w1, 33, 34x. In experimental stroke, young female animals show less damage than young males w35–39x. However, this sex difference is not observed in older individuals w40x. Human studies indicate that the incidence of stroke is higher in men than in women. However, after 85 years of age, there is a higher incidence of stroke in women w41x, which may be in part due to the fact that women have strokes at older ages than men. In addition, women have a poorer recovery from stroke than men w33, 34, 42–45x. However, while some studies suggest increased long-term mortality in women vs. men after stroke, other studies indicate the opposite w33, 34, 41, 46–48x. Sex differences in the outcome of traumatic brain injury
Some observations indicate that mortality and poor outcomes (i.e., severe disability or persistent vegetative state) after traumatic brain injury were significantly higher in females than in males with the same extent of injury w49–51x; however, others seem to suggest the opposite. Thus, females have better overall responses to rehabilitation therapy w52x. Moreover, as indicated by the Glasgow Coma Scale scores and length of post-traumatic amnesia, men have greater level of injury w53x. Similar results were obtained using the Wisconsin card sort test as a measure of executive function w54x. Furthermore, 1 year from injury women show better performance on cognitive outcome measures w55x. Finally, further observations indicate that, after moderate-to-severe traumatic brain injury, outcomes are significantly worse in age-matched males than in post-menopausal females. This difference is not observed when males and pre-menopausal females are compared w56x. Interesting observations have also been obtained in cerebral spinal fluid of patients. These suggest that females have smaller oxidative damage loads than males w57x, and a significant sex difference also occurs
in glutamate and lactate/pyruvate production w58x and in lipid peroxidation w59x.
Possible causes of sex differences in brain pathology Sexual differentiation of the nervous system
Sex differences in brain pathology may be the consequence of the morphological and functional differences in neural structure between the sexes w60x. Both genetic sex and developmental actions of sex hormones contribute to the generation of these sex differences w61–63x and both factors may therefore influence the risk and outcome of neurodegenerative and neurological diseases w1, 64, 65x. The importance of genetically-determined or hormonally-generated sex differences in neural cells in the sexually dimorphic response of the nervous system to injury is suggested by the existence of sex differences in the in vitro response of neurons, glial cells, and brain slices to damaging agents w66–69x. In addition, stress hormones during the developmental period may affect brain differentiation and may have permanent effects on brain function. Thus, pre-natal stress and maternal separation have been reported to affect the structure and function of different brain regions w70–72x. The alterations caused by pre-natal and early post-natal stress may contribute to facilitate brain deterioration with aging w72x. Interestingly, pre-natal and early post-natal stress have different consequences in males and females w70, 71, 73x, and may contribute to the generation of sex differences in brain pathology. Sex differences in gene expression in adulthood
In addition to the influence of sex determination genes in the differentiation of the brain, the expression of genes located in the Y chromosome during adulthood w74x is a potential source of sex differences in brain pathology. Furthermore, the partial inactivation of X-linked chromosome genes in females w75x may also generate differences in brain gene expression during adult life w74x that, in turn, may influence the response of neural tissue to injury and degeneration w76x. The influence of the steroid milieu in adulthood
Neuroactive steroids exert neuroprotective actions w1, 77–83x. Therefore, changes in the levels of sex steroid hormones during the ovarian cycle and aging may contribute to the generation of sex differences in the manifestation of brain pathology. Indeed, in female rodents it has been demonstrated that the fluctuation in hormonal levels during the estrous cycle affects the response of the brain to pathological insults. For instance, the neurotoxic effect of kainic acid on hippocampal neurons in intact female rats is different depending on the day of the estrous cycle on which the neurotoxin is injected. No significant neuronal loss is observed when a moderate dose of kainic acid is injected on the morning of estrus, 1 day after the peak of estrogen levels in plasma. In
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contrast, there is a significant loss of hilar neurons when the same dose of kainic acid is injected in the morning of proestrus, before the peak of estrogen levels in plasma, as well as when it is injected into ovariectomized rats w84x. Both circulating testosterone and estradiol as well as estradiol locally synthesized within the brain have been shown to exert neuroprotective effects in this experimental model of neurodegeneration w85x. Animals injected with kainic acid may develop seizures and, as we have mentioned previously, the administration of this neurotoxin to rodents is often used as a model of epilepsy. Interestingly, seizures involving the limbic system are also influenced by the menstrual cycle in epileptic women w65x; seizure activity incidence is low when progesterone levels in plasma are high compared to estradiol levels. In contrast, seizure activity is higher when both progesterone and estradiol are at low levels in plasma and during the follicular phase, when there is an abrupt increase in estradiol plasma levels w65, 86x. Sex steroid hormones may be involved in sex differences in the outcome of experimental stroke, because the damage in female animals is enhanced by ovariectomy w39x. However, the balance of androgens and estrogens may also determine sex differences in the outcome of neurodegeneration since androgens enhance brain damage induced by middle cerebral artery occlusion in male animals w87–89x. This may also be the case in other pathologies. For instance, decreased levels of estradiol correlate with an increased neurodegeneration in males in an experimental rat model of Huntington disease w8x. The balance of estrogens and androgens seems also to determine the sexual dimorphism on the neurodegenerative effect of the non-competitive NMDA receptorantagonist MK801 in the granular retrosplenial cortex of rats, which is more manifest in females w90x. In this case, however, androgens seem to inhibit and estradiol seems to increase neurodegeneration. In a model of Parkinson’s disease, caused by the lesion of the nigrostriatal dopaminergic pathway with 6-hydroxydopamine, estrogen is neuroprotective in females but not in males w91, 92x. However, local production of estradiol within the brain appears to protect against neurotoxin-induced striatal damage in both male and female rodents w93, 94x. Sex differences in the response of the striatal dopaminergic system to estradiol may be in part the consequence of sex differences in the structural and functional organization of the dopaminergic synaptic circuits w91x. However, the causes for the different outcome of central and peripheral estradiol in males remain to be elucidated. On the other hand, neuronal damage in female rodents in experimental models of Parkinson’s disease is influenced by the endogenous fluctuation of gonadal hormones during the estrous cycle w91, 95–97x. In addition, regulation of estrogen receptor alpha turnover by the Parkinson’s disease-related protein parkin may also be involved in the sex difference in this neurodegenerative disease w98x. Therefore, both sex differences in the organization of the nigrostriatal dopaminergic system, sex differences in circulating hormones, and sex differences in the sensitivity and response of neural tissue to these hormones may contribute to determine sex differences in the manifestation of the pathology.
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It is also important to consider that brain injury affects the levels of neuroactive steroids in the nervous system and plasma w99, 100x. The regulation of the levels of neuroactive steroids after neural injury may present sexually dimorphic profiles and may be affected by the endocrine status of the animals w101–104x. Sex differences in brain steroid levels after injury may be the consequence of sex differences in the expression and/or activity of steroidogenic enzymes in the nervous system. For instance, sex differences in the expression and activity of the enzyme aromatase in astrocytes has been reported. This finding suggests that astrocytes from female brains produce more estradiol than astrocytes from males w69x. Because aromatase expression in astrocytes is induced after brain injury and is neuroprotective w80–82, 85x, the reported sex differences in the expression of aromatase by astrocytes may be relevant to explain sex differences in the manifestation of brain pathologies and to explain sex differences in the response of the injured male and female brain to estradiol therapy. In addition to sex differences in peripheral or central steroid levels, sex differences in the response of neurons and glial cells to hormonal steroids may also be involved in the manifestation of sex differences in brain pathology. Sex differences in the action of glucocorticoids in the brain may contribute to the generation of sex differences in brain damage. It has been proposed that the female brain has a different innate strategy to handle stress than the male brain w73, 105x. An enhanced corticosterone response in females may be the cause of sex differences in cognitive performance in an experimental model of Alzheimer’s disease w5x. Neurons and glial cells also show a sexually dimorphic response to gonadal hormones. For instance, repeated estradiol pulses modulate hippocampal neurogenesis and neuronal death in adult female rodents but not in adult male rodents, while testosterone and dihydrotestosterone upregulate hippocampal neurogenesis in adult male rodents w106x. In addition, gonadal hormones have different effects in the survival of oligodendrocytes in cultures from female mice compared to cultures from male mice w107x. Estradiol has more potent effects in decreasing proliferation and increasing cell death in primary cortical astrocytic cultures from females than in astrocytes from males w108x. These differences may be highly relevant for demyelinating diseases and other pathological conditions in which white matter is affected. The differential effects of glucocorticoids and sex steroid hormones in male and female neural cells may be a consequence of the existence of sex differences in the levels of steroid receptors or in the mechanisms of steroid signaling. For instance, progesterone, estradiol, and dihydrotestosterone have different effects in the activation of Akt in male and female oligodendrocytes w107x and estradiol has different effects on the activation of ERK1 and ERK2 in male and female astrocytes w108x. In addition, male and female brains may respond to injury with different changes in the expression of steroid receptors. Thus, sex differences in the damage produced in the cerebral cortex by middle cerebral artery occlusion may be associated with sex differences in the regulation of estrogen receptor alpha expression, which is
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increased in the cerebral cortex of female rats, but not in males, after the brain injury w109x. 2.
The influence of the immune system
Sex differences in immune responses w110x, including sex differences in CNS immunity w111x, may contribute to different outcome of pathological insults to the brain and the spinal cord. Sex differences in pro-inflammatory responses, which have been described in multiple sclerosis patients w112, 113x and in experimental autoimmune encephalomyelitis w114–117x, may contribute to the sex differences in the manifestation of the pathology. Indeed, MRI analyses have shown that men develop less inflammatory, but more destructive, lesions than women w118x. Sex differences in the inflammatory response also contribute to the generation of sex differences in brain damage in experimental models of Alzheimer’s w119x, Parkinson’s w120x, and cerebrovascular disease w121x. Both glucocorticoids and sex steroid hormones are known to regulate the inflammatory responses of astrocytes, microglia, and peripheral immune cells w110, 122, 123x, and may therefore be involved in the generation of sex differences in CNS immunity.
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Concluding remarks 8.
We have here reviewed evidence indicating that the pathological manifestations of the central nervous system after injury and under neurodegenerative conditions present sexually dimorphic traits. We have also analyzed some potential causes for these differences, in particular the influence of genetic, endocrine, and immune factors. However, there are other variables that have not been reviewed here, such as sex differences in behavior, which are not always associated to reproduction. It is becoming evident that physical exercise and other factors associated to individual’s attitudes, including diet and drug consumption, may affect cognition and the outcome of brain pathology. In humans, cultural factors that impose different behavioral patterns in men and women may result in gender differences in life style, which in turn may generate gender differences in the risk of neurodegenerative diseases and brain injury. These and other factors should be further explored to understand the causes of sex differences in brain pathology, with the final aim of developing genderspecific strategies to prevent and counteract central nervous system damage.
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Acknowledgements The financial support of Fondazione San Paolo (Progetto Neuroscienze, PF-2009.1180), Fondazione Italiana Sclerosi Multipla (2010/ 23) and PUR from Universita degli Studi di Milano, Italy, to R.C. Melcangi is gratefully acknowledged.
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Sex differences in the injured brain
Roberto Cosimo Melcangi1,* and Luis M. GarciaSegura2 1
Department of Endocrinology, Pathophysiology and Applied Biology – Center of Excellence on Neurodegenerative Diseases, Universita` degli Studi di Milano, Milano, Italy 2 Instituto Cajal, C.S.I.C., Avenida Doctor Arce 37, Madrid, Spain
Abstract Observations obtained in human and in experimental models clearly demonstrate sex differences in degenerative events occurring in the central nervous system. The present review focuses on potential factors that may contribute to these sex-dimorphic features; in particular, morphological organization of the central nervous system and functional influence by neuroactive steroids, genes, and immune system are considered.
expression of specific genes in the adult central nervous system. Sex differences in the levels of steroid hormones, neurosteroids (i.e., steroids synthesized in the nervous system), and neuroactive steroids (i.e., a definition including both steroid hormones and neurosteroids) in adulthood is the factor that has been explored in more detail, since there is solid evidence indicating that these hormones may affect the outcome of insults to the brain and the spinal cord. Finally, sex differences in the immune system have been reported. This is a critical factor for the manifestation of sex differences in autoimmune diseases and may also be relevant for other inflammatory conditions. We will briefly review here some representative examples of sex differences in brain pathology, with information obtained from clinical and animal studies. Then we will analyze the potential influence of the factors mentioned above in the generation of these differences.
Sex differences in brain pathology Keywords: gender; inflammation; neuroactive steroids; neurodegenerative diseases.
Introduction Clinical evidence and studies in animal models of central nervous system injury and neurodegeneration have revealed the existence of sex differences in the pathology of the brain and the spinal cord. These differences may be manifested in the age of onset, incidence, prevalence, or prognosis of the disease, in the tissue damage associated with the pathological condition, and/or in the response to rehabilitation or neuroprotective therapies. There are several potential factors that may contribute to generate sex differences in brain pathology. One of these factors is the existence of sex differences in the functional and morphological organization of the central nervous system. These differences are generated during the developmental period and may be the direct consequence of the expression by neural cells of specific sex differentiation genes. In addition, steroid milieu regulates the process of sex differentiation of the brain and the spinal cord. Another potential source for sex differences in brain pathology, although less explored, is the sexually dimorphic *Corresponding author: Roberto Cosimo Melcangi, Department of Endocrinology, Pathophysiology and Applied Biology – Center of Excellence on Neurodegenerative Diseases, Universita` degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy Phone: q39-02-50318238, Fax: q39-02-50318204, E-mail: [email protected] Received May 28, 2011; accepted July 6, 2011; previously published online August 15, 2011
Sex differences in the incidence and manifestation of neurodegenerative diseases
Studies in different animal models of neurodegenerative diseases have revealed the existence of sex differences in brain damage w1x. In some cases females are more affected by the pathology than males. For instance, female mice show higher seizure activity and more hippocampal neurodegeneration than male mice after the administration of kainic acid, a model of epilepsy and of excitotoxic neurodegeneration w2x. In addition, females show higher plaque load than males in different amyloid precursor protein (APP) transgenic animal models of Alzheimer’s disease w3, 4x. In transgenic mice expressing mutant APP, preselinin-1, and tau, female animals show an increased cognitive impairment w5x and an increased production and decreased degradation of b-amyloid compared to males w6x. In contrast, in a model of Parkinson’s disease in mice, caused by the intoxication with 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine, male animals show a greater depletion of dopamine than female animals w7x. Also, in transgenic animal models of Huntington’s disease, males show greater motor deficits and increased loss and atrophy of dopaminergic neurons than females w8, 9x. Sex differences in the incidence and manifestation of neurodegenerative diseases have been observed in humans w1x. The incidence of Parkinson’s disease is greater in men than in women w10–13x, and women present higher age at onset and milder motor deterioration than men w14x. Age of onset of Huntington’s disease is also higher and the course of the illness more moderate in women than in men w15–17x. In contrast, epidemiological studies support a higher prevalence
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and incidence of Alzheimer’s disease in women w18–21x. Sex differences in Alzheimer’s disease patients are also evidenced in terms of plaque load, with a significantly different distribution of them in cortical areas of female patients w22x. Women also show more neurofibrillary tangles w23x. Analysis of visuospatial episodic memory also shows sex differences, with a better performance in male than in female Alzheimer’s disease patients w24x. Clinical manifestation of dementia among Alzheimer’s disease patients is more common in women than in men w23x. As it has been reported for other autoimmune diseases w25x, the incidence of multiple sclerosis is higher in women than in men w26–28x. However, men have a worse prognosis than women w29x. Indeed, men are affected in older age and develop a more severe pathology, defined as a shorter time to reach severe disability w30x. Cognitive decline is also more predominant in men than in women w31, 32x. Sex differences in the incidence and outcome of stroke
Stroke is another pathological condition for which sex differences in the underlying etiology, presentation, and outcome have been reported w1, 33, 34x. In experimental stroke, young female animals show less damage than young males w35–39x. However, this sex difference is not observed in older individuals w40x. Human studies indicate that the incidence of stroke is higher in men than in women. However, after 85 years of age, there is a higher incidence of stroke in women w41x, which may be in part due to the fact that women have strokes at older ages than men. In addition, women have a poorer recovery from stroke than men w33, 34, 42–45x. However, while some studies suggest increased long-term mortality in women vs. men after stroke, other studies indicate the opposite w33, 34, 41, 46–48x. Sex differences in the outcome of traumatic brain injury
Some observations indicate that mortality and poor outcomes (i.e., severe disability or persistent vegetative state) after traumatic brain injury were significantly higher in females than in males with the same extent of injury w49–51x; however, others seem to suggest the opposite. Thus, females have better overall responses to rehabilitation therapy w52x. Moreover, as indicated by the Glasgow Coma Scale scores and length of post-traumatic amnesia, men have greater level of injury w53x. Similar results were obtained using the Wisconsin card sort test as a measure of executive function w54x. Furthermore, 1 year from injury women show better performance on cognitive outcome measures w55x. Finally, further observations indicate that, after moderate-to-severe traumatic brain injury, outcomes are significantly worse in age-matched males than in post-menopausal females. This difference is not observed when males and pre-menopausal females are compared w56x. Interesting observations have also been obtained in cerebral spinal fluid of patients. These suggest that females have smaller oxidative damage loads than males w57x, and a significant sex difference also occurs
in glutamate and lactate/pyruvate production w58x and in lipid peroxidation w59x.
Possible causes of sex differences in brain pathology Sexual differentiation of the nervous system
Sex differences in brain pathology may be the consequence of the morphological and functional differences in neural structure between the sexes w60x. Both genetic sex and developmental actions of sex hormones contribute to the generation of these sex differences w61–63x and both factors may therefore influence the risk and outcome of neurodegenerative and neurological diseases w1, 64, 65x. The importance of genetically-determined or hormonally-generated sex differences in neural cells in the sexually dimorphic response of the nervous system to injury is suggested by the existence of sex differences in the in vitro response of neurons, glial cells, and brain slices to damaging agents w66–69x. In addition, stress hormones during the developmental period may affect brain differentiation and may have permanent effects on brain function. Thus, pre-natal stress and maternal separation have been reported to affect the structure and function of different brain regions w70–72x. The alterations caused by pre-natal and early post-natal stress may contribute to facilitate brain deterioration with aging w72x. Interestingly, pre-natal and early post-natal stress have different consequences in males and females w70, 71, 73x, and may contribute to the generation of sex differences in brain pathology. Sex differences in gene expression in adulthood
In addition to the influence of sex determination genes in the differentiation of the brain, the expression of genes located in the Y chromosome during adulthood w74x is a potential source of sex differences in brain pathology. Furthermore, the partial inactivation of X-linked chromosome genes in females w75x may also generate differences in brain gene expression during adult life w74x that, in turn, may influence the response of neural tissue to injury and degeneration w76x. The influence of the steroid milieu in adulthood
Neuroactive steroids exert neuroprotective actions w1, 77–83x. Therefore, changes in the levels of sex steroid hormones during the ovarian cycle and aging may contribute to the generation of sex differences in the manifestation of brain pathology. Indeed, in female rodents it has been demonstrated that the fluctuation in hormonal levels during the estrous cycle affects the response of the brain to pathological insults. For instance, the neurotoxic effect of kainic acid on hippocampal neurons in intact female rats is different depending on the day of the estrous cycle on which the neurotoxin is injected. No significant neuronal loss is observed when a moderate dose of kainic acid is injected on the morning of estrus, 1 day after the peak of estrogen levels in plasma. In
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contrast, there is a significant loss of hilar neurons when the same dose of kainic acid is injected in the morning of proestrus, before the peak of estrogen levels in plasma, as well as when it is injected into ovariectomized rats w84x. Both circulating testosterone and estradiol as well as estradiol locally synthesized within the brain have been shown to exert neuroprotective effects in this experimental model of neurodegeneration w85x. Animals injected with kainic acid may develop seizures and, as we have mentioned previously, the administration of this neurotoxin to rodents is often used as a model of epilepsy. Interestingly, seizures involving the limbic system are also influenced by the menstrual cycle in epileptic women w65x; seizure activity incidence is low when progesterone levels in plasma are high compared to estradiol levels. In contrast, seizure activity is higher when both progesterone and estradiol are at low levels in plasma and during the follicular phase, when there is an abrupt increase in estradiol plasma levels w65, 86x. Sex steroid hormones may be involved in sex differences in the outcome of experimental stroke, because the damage in female animals is enhanced by ovariectomy w39x. However, the balance of androgens and estrogens may also determine sex differences in the outcome of neurodegeneration since androgens enhance brain damage induced by middle cerebral artery occlusion in male animals w87–89x. This may also be the case in other pathologies. For instance, decreased levels of estradiol correlate with an increased neurodegeneration in males in an experimental rat model of Huntington disease w8x. The balance of estrogens and androgens seems also to determine the sexual dimorphism on the neurodegenerative effect of the non-competitive NMDA receptorantagonist MK801 in the granular retrosplenial cortex of rats, which is more manifest in females w90x. In this case, however, androgens seem to inhibit and estradiol seems to increase neurodegeneration. In a model of Parkinson’s disease, caused by the lesion of the nigrostriatal dopaminergic pathway with 6-hydroxydopamine, estrogen is neuroprotective in females but not in males w91, 92x. However, local production of estradiol within the brain appears to protect against neurotoxin-induced striatal damage in both male and female rodents w93, 94x. Sex differences in the response of the striatal dopaminergic system to estradiol may be in part the consequence of sex differences in the structural and functional organization of the dopaminergic synaptic circuits w91x. However, the causes for the different outcome of central and peripheral estradiol in males remain to be elucidated. On the other hand, neuronal damage in female rodents in experimental models of Parkinson’s disease is influenced by the endogenous fluctuation of gonadal hormones during the estrous cycle w91, 95–97x. In addition, regulation of estrogen receptor alpha turnover by the Parkinson’s disease-related protein parkin may also be involved in the sex difference in this neurodegenerative disease w98x. Therefore, both sex differences in the organization of the nigrostriatal dopaminergic system, sex differences in circulating hormones, and sex differences in the sensitivity and response of neural tissue to these hormones may contribute to determine sex differences in the manifestation of the pathology.
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It is also important to consider that brain injury affects the levels of neuroactive steroids in the nervous system and plasma w99, 100x. The regulation of the levels of neuroactive steroids after neural injury may present sexually dimorphic profiles and may be affected by the endocrine status of the animals w101–104x. Sex differences in brain steroid levels after injury may be the consequence of sex differences in the expression and/or activity of steroidogenic enzymes in the nervous system. For instance, sex differences in the expression and activity of the enzyme aromatase in astrocytes has been reported. This finding suggests that astrocytes from female brains produce more estradiol than astrocytes from males w69x. Because aromatase expression in astrocytes is induced after brain injury and is neuroprotective w80–82, 85x, the reported sex differences in the expression of aromatase by astrocytes may be relevant to explain sex differences in the manifestation of brain pathologies and to explain sex differences in the response of the injured male and female brain to estradiol therapy. In addition to sex differences in peripheral or central steroid levels, sex differences in the response of neurons and glial cells to hormonal steroids may also be involved in the manifestation of sex differences in brain pathology. Sex differences in the action of glucocorticoids in the brain may contribute to the generation of sex differences in brain damage. It has been proposed that the female brain has a different innate strategy to handle stress than the male brain w73, 105x. An enhanced corticosterone response in females may be the cause of sex differences in cognitive performance in an experimental model of Alzheimer’s disease w5x. Neurons and glial cells also show a sexually dimorphic response to gonadal hormones. For instance, repeated estradiol pulses modulate hippocampal neurogenesis and neuronal death in adult female rodents but not in adult male rodents, while testosterone and dihydrotestosterone upregulate hippocampal neurogenesis in adult male rodents w106x. In addition, gonadal hormones have different effects in the survival of oligodendrocytes in cultures from female mice compared to cultures from male mice w107x. Estradiol has more potent effects in decreasing proliferation and increasing cell death in primary cortical astrocytic cultures from females than in astrocytes from males w108x. These differences may be highly relevant for demyelinating diseases and other pathological conditions in which white matter is affected. The differential effects of glucocorticoids and sex steroid hormones in male and female neural cells may be a consequence of the existence of sex differences in the levels of steroid receptors or in the mechanisms of steroid signaling. For instance, progesterone, estradiol, and dihydrotestosterone have different effects in the activation of Akt in male and female oligodendrocytes w107x and estradiol has different effects on the activation of ERK1 and ERK2 in male and female astrocytes w108x. In addition, male and female brains may respond to injury with different changes in the expression of steroid receptors. Thus, sex differences in the damage produced in the cerebral cortex by middle cerebral artery occlusion may be associated with sex differences in the regulation of estrogen receptor alpha expression, which is
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increased in the cerebral cortex of female rats, but not in males, after the brain injury w109x. 2.
The influence of the immune system
Sex differences in immune responses w110x, including sex differences in CNS immunity w111x, may contribute to different outcome of pathological insults to the brain and the spinal cord. Sex differences in pro-inflammatory responses, which have been described in multiple sclerosis patients w112, 113x and in experimental autoimmune encephalomyelitis w114–117x, may contribute to the sex differences in the manifestation of the pathology. Indeed, MRI analyses have shown that men develop less inflammatory, but more destructive, lesions than women w118x. Sex differences in the inflammatory response also contribute to the generation of sex differences in brain damage in experimental models of Alzheimer’s w119x, Parkinson’s w120x, and cerebrovascular disease w121x. Both glucocorticoids and sex steroid hormones are known to regulate the inflammatory responses of astrocytes, microglia, and peripheral immune cells w110, 122, 123x, and may therefore be involved in the generation of sex differences in CNS immunity.
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Concluding remarks 8.
We have here reviewed evidence indicating that the pathological manifestations of the central nervous system after injury and under neurodegenerative conditions present sexually dimorphic traits. We have also analyzed some potential causes for these differences, in particular the influence of genetic, endocrine, and immune factors. However, there are other variables that have not been reviewed here, such as sex differences in behavior, which are not always associated to reproduction. It is becoming evident that physical exercise and other factors associated to individual’s attitudes, including diet and drug consumption, may affect cognition and the outcome of brain pathology. In humans, cultural factors that impose different behavioral patterns in men and women may result in gender differences in life style, which in turn may generate gender differences in the risk of neurodegenerative diseases and brain injury. These and other factors should be further explored to understand the causes of sex differences in brain pathology, with the final aim of developing genderspecific strategies to prevent and counteract central nervous system damage.
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Acknowledgements The financial support of Fondazione San Paolo (Progetto Neuroscienze, PF-2009.1180), Fondazione Italiana Sclerosi Multipla (2010/ 23) and PUR from Universita degli Studi di Milano, Italy, to R.C. Melcangi is gratefully acknowledged.
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