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Indian Journal of Pharmacology, Vol. 36, No. 2, April, 2004, pp. 98-99 Research Letter Is oestrogen a ‘biological neuroprotective’? Chattopadhyay S Medical Officer, B. C. Roy Technology Hospital, Indian Institute of Technology, Kharagpur - 721302 Code Number: ph04036 Sir, The present article outlines two interesting observations related to schizophrenia research: A. The biological ′sex bias′ i.e. males usually develop the illness early,[1] sustain a more vulnerable course and often have poorer prognosis than females.[2] On the other hand, females develop the illness during their lifetime when the serum estrogen level is low, for example at a particular phase of the menstrual cycle,[3] after childbirth[4] and after menopause.[5] B. Despite equal exposure to birth-related complications male babies are more vulnerable to schizophrenia than females.[6] Therefore, it would be appropriate to surmise that females are blessed with some ′biological boon′ which is absent in males. Researchers have studied many factors (genetic, anatomical, epidemiological, socio-cultural and biological) that could be involved in such male-female heterogeneity in the schizophrenic population. This article emphasizes the possible role of estrogen as a biological variable in the pathophysiology of schizophrenia. Estrogen is known to influence the pathophysiology of several diseases including psychiatric illnesses through its nuclear receptor gene expression. Genetic studies of estrogen metabolism show that estrogen is responsible for breast, endometrial and colorectal cancers, polycystic ovarian disease (PCOD), Parkinson′s disease, alcoholism and schizophrenia.[7] Studies have also shown the symptom-alleviating roles of oral estrogen therapy in postmenopausal females,[8] of transdermal estrogen in puerperal psychosis[9] and female schizophrenics,[10] and of estrogen-progesterone combined pills in schizophrenic females having PCOD[11] and premenstrual tension.[12] Many studies have shown that the level of serum estrogen has got a strong correlation with cognitive function, especially global cognition, verbal, spatial deceleration, memory and perceptual motor speech. Further, higher estrogen levels in female schizophrenics are associated with better cognitive ability.[13] While evaluating the molecular process of such benefits of estrogen in the brain, it has been observed that estrogen prevents toxin-related neuronal degenerations, maintains normal neuronal growth and thus may have tremendous implications in alcoholism, Alzheimer′s disease, mood disorders and schizophrenia.[14] It has also been found that estrogen prevents several neurodegenerative processes by virtue of its nuclear receptor-mediated-alteration of estrogen-responsive-gene-expression that modulates the rate of apoptosis, axonal degeneration and offers a generalized support to the neurons.[15] A recent study has found that synthetic conjugated estrogens exert some neuroprotective effects in the brain and prevent the insult related to Alzheimer′s disease.[16] Another study has shown that estrogen also protects retinal ganglionic cell lines from ischemia-induced-damage observed especially in sickle cell disease and diabetes-induced retinopathies.[17] Moreover, it is also seen that estrogen has a potent antioxidant effect as it moderates the potency of superoxide dismutase (an antioxidant enzyme) in the circulating monocytes and reduces the amount of free radicals.[18] Therefore, it can be inferred that estrogen physiologically confers a neuroprotective effect on the female brain due to its biological abundance. Detailed studies on the pathophysiology of schizophrenia hypothesize excessive dopaminergic activity in the mesolimbic and mesocortical regions of the brain along with other neurotransmitters, like serotonin and GABA.[19] In this context, a large number of studies have shown that estrogen has modulating roles on dopamine and serotonin receptors in the relevant part of the brain affected in schizophrenia. In support of such postulations and to understand the molecular mechanisms of estrogenic action at the cerebral neurotransmitter level the following animal studies have been reviewed. Studies on animal models have shown that estrogen is a potent dopamine receptor blocker, especially D1 and D2.[20] A few studies had also mentioned that estrogen is a potent GABA-A receptor manipulator and thus reduces the load of tardive dyskinesia due to antipsychotic drugs.[20] A series of studies have documented that apart from dopamine and GABA, estrogen can also block serotonin receptors, especially 5-HT1A and 5-HT2A.[21],[22],[23],[24],[25] One study has shown that progesterone also expresses D5 receptors in the atrial natriuretic peptide neurons in the hypothalamus although the effect is less potent than estrogen.[26] The authors mention that there might be a possibility that progesterone could enhance the effect of estrogen[26] and thus it could lead to an estrogen-progesterone combination therapy in schizophrenia! It is possible to infer that estrogen is a natural neuroprotectant and by blocking dopamine and serotonin neuroreceptors in the brain, probably acts in a manner similar to neuroleptics, which are either purely dopamine blockers (e.g. chlorpromazine, haloperidol and clozapine) or dopamine plus serotonin blockers (e.g. risperidone). Estrogen is thus better called a schizoprotectant, as it not only prevents the development of schizophrenia but also improves the external psychological functioning in the patients. Although a large body of studies has substantiated this view, it needs to be tested further on a large sample of first-onset drug-naïve female schizophrenics (preferably post-menopausal) using an interdisciplinary program. REFERENCES
Copyright 2004 - Indian Journal of Pharmacology |
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