Ayanabha Chakraborti

Possible involvement of free radicals in the differential neurobehavioral responses to stress in male and female rats

The effect of restraint stress (RS) on neurobehavioral and brain oxidative stress parameters, and their modulation by antioxidants were evaluated in male and cycling female rats. Exposure to RS suppressed both open arm entries and open arm time in the elevated plus maze and these changes were more marked in males than in females. Assay of brain homogenates revealed that the behavioral suppression was associated with similar differential increases in malondialdehye (MDA) and decreases in glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels in males and females. Pretreatment with alpha-tocopherol (25 and 50 mg/kg) and N-acetylcysteine (100 and 200 mg/kg), attenuated the stress induced alteration of behavioral and oxidative stress markers in a consistent manner in both male and female rats. These findings suggest that males may be more susceptible than females to stress induced neurobehavioral changes and free radicals may exert a regulatory influence in such gender dependent responses to stress.

Age related differences in stress-induced neurobehavioral responses in rats: modulation by antioxidants and nitrergic agents.

The effect of restraint stress (RS) on neurobehavioral and brain oxidative/nitrosative stress markers and their modulation by antioxidants and nitrergic agents were evaluated in young (2 months) and old (16 months) male Wistar rats. Exposure to RS, induced anxiogenesis when tested in the elevated plus maze (EPM) and open field (OF) tests and such changes were greater in the old as compared to the young rats. These behavioral alterations were associated with enhanced levels of malondialdehyde (MDA) and reductions in glutathione (GSH), catalase (CAT) and nitric oxide metabolites (NOx) levels in brain homogenates-the effects being greater in intensity in the old as compared to the young animals. Pretreatment with antioxidants, alpha-tocopherol (25 and 50mg/kg) and N-acetylcysteine (100 and 200mg/kg) consistently reversed the RS-induced behavioral and biochemical alterations in both young and old rats. Similar attenuations of RS-induced changes were seen after pretreatment with NO precursor L-arginine (500 and 1000mg/kg) while the NO synthase inhibitor N-nitro L-arginine methyl ester (L-NAME) (50 and 100mg/kg) tended to aggravate the effects of RS in both age groups of rats. The results suggest that susceptibility to stress-induced neurobehavioral alterations may increase with age and interactions of reactive oxygen species (ROS) and nitric oxide in the central nervous system may exert a regulatory influence in such age dependent responses to stress.

Modulation of stress-induced neurobehavioral changes and brain oxidative injury by nitric oxide (NO) mimetics in rats

The present study evaluated the effects of NO mimetics on stress-induced neurobehavioral changes and the possible involvement of ROS-RNS interactions in rats. Restraint stress (RS) suppressed both percent open arm entries and time spent in the open arms in the elevated plus maze (EPM) test. These RS-induced changes in EPM activity were attenuated by the NO mimetics, l-arginine, isosorbide dinitrate and molsidomine, in a differential manner. RS-exposed rats showed (a) increased lipid peroxidation (MDA) and (b) lowered reduced glutathione (GSH) and NO metabolites (NOx), in brain homogenates of these animals. Pretreatment with the NO mimetics also differentially influenced RS-induced changes in brain oxidative stress markers. The results suggest that NO may protect against stress-induced anxiogenic behavior and oxidative injury in the brain and highlight the significance of ROS-RNS interactions.

Differential role of nitric oxide (NO) in acute and chronic stress induced neurobehavioral modulation and oxidative injury in rats.

The present study evaluated the effects of acute and chronic restraint stress (RS 1 h or 6 h), and their modulation by nitrergic agents on neurobehavioral and oxidative stress markers in rats. Acute RS (1 h or 6 h) reduced open arm entries (OAE) and open arm time (OAT) in the elevated plus maze test - which were attenuated by the NO precursor, L-arginine but not influenced appreciably by the NO synthase inhibitor, L-NAME. These behavioral changes were associated with differential changes in brain NO metabolites (NOx) but consistently reduced GSH and raised MDA levels in comparison to the control group. Following RS 1 h x 10 the neurobehavioral suppression and changes in brain oxidative stress markers were less pronounced as compared to the acute RS (1 h) group indicating adaptation. L-arginine pretreatment facilitated this adaptation to chronic RS (1 h). Interestingly RS 6 h x 10, induced severe behavioral suppression and aggravation of MDA and NOx levels and L-NAME pretreatment tended to protect against these chronic RS induced aggravations. These results suggest that acute and chronic RS induces duration/intensity dependent neurobehavioral and oxidative injury which are under the differential regulatory control of NO.

Involvement of nitric oxide in the protective effects of dehydroepiandrosterone sulphate on stress induced neurobehavioral suppression and brain oxidative injury in rats.

The involvement of nitric oxide (NO) in the effects of dehydroepiandrosterone sulphate (DHEAS) on restraint stress induced neurobehavioral and brain oxidative/nitrosative stress markers was investigated in rats. Exposure of rats to restraint stress suppressed behavioral activity in the elevated plus maze and this was associated with increases in malondialdehyde (MDA) and decrease in reduced glutathione (GSH) and brain NO metabolite (NOx) levels in brain homogenates. Pretreatment with DHEAS (5-40mg/s.c.) reversed the stress induced changes in behavioral and oxidative stress markers and also brain NOx levels. The beneficial effect of DHEAS (40mg/kgs.c.) was blocked by pretreatment with nitric oxide synthase inhibitor, L-NAME (50mg/kgi.p.) while pretreatment of rats with NO-precursor l-Arginine (100mg/kg i.p.) produced potentiation of action of sub effective dose of DHEAS (5mg/kgs.c.). The DHEAS effects were stress specific as these behavioral and biochemical parameters were not much influenced in non-stressed rats. These observations suggest that pretreatment with DHEAS has a protective effect on restraint stress induced alteration of neurobehavioral changes and brain oxidative injury in rats and NO-dependent mechanisms may be involved in this effect.

Estrogen actions on brain and behavior: recent insights and future challenges.

Recent advances in our knowledge of estrogen action in the brain suggest that this steroid is not solely an endocrine factor but plays important but hitherto largely unrecognized physiological and pathophysiological roles that are not directly involved in reproductive processes. Estrogens are now known to influence a wide variety of functions in the mammalian brain ranging from regulation of various aspects of neurotransmitter function and modulation of behaviour to the stimulation of differentiation and plasticity of distinct neuronal populations and circuits. Acting via both genomic and nongenomic mechanisms estrogens can influence higher cognitive functions, pain mechanisms, fine motor skills, mood, susceptibility to. seizures, and also appear to have important neuroprotective function in relation to stroke damage and neurodegenerative disorders. This review focuses on new advancements from clinical and basic studies on estrogen action in the central nervous system especially illustrating the brain regions and cell types in which estrogens produce their effects, emphasizing new knowledge regarding estrogen actions outside the hypothalamus and pituitary gland. Current therapeutic strategies to develop suitable estrogen receptor modulators with a selective spectrum of action in the brain and priorities for future research are also briefly discussed.

Possible role of nitric oxide (NO) in the regulation of gender related differences in stress induced anxiogenesis in rats

Gender related differences in stress induced neurobehavioral disorders have been reported although the mechanisms involved are not yet clear. The present study investigated the role of nitric oxide, an important biomodulator in the sex related differences in stress induced anxiety like behavior in rats. Restraint stress (RS for 1 h) was used as the experimental stressor and the effects of NO modulators were assessed in the elevated plus maze (EPM) test in both male and female rats. No metabolites (NOx) and asymmetric dimethyl arginine (ADMA) were measured in brain homogenates of these rats for corroborative purposes. RS induced anxiogenesis in both male and female rats and such changes were greater in males as compared to females. The behavioral alterations were associated with enhanced levels of ADMA and reductions in levels of NOx in brain homogenates - the effects being greater in intensity in males as compared to females. Pretreatment with NO precursor L-arginine (500 mg/kg) reversed the RS induced behavioral and biochemical changes, while NO synthase inhibitor L-NAME (50 mg/kg) had opposite effects. Additionally, Formestane (50 mg/kg), an estrogen synthesis blocker, aggravated stress induced anxiogenesis with a corresponding increase in ADMA and decrease in NOx levels in the females. To our knowledge, this is the first report indicating the involvement of ADMA, an endogenous nitric oxide synthase inhibitor in stress induced neurobehavioral changes. Furthermore, it is also evident that nitric oxide and its interactions with estrogens play a crucial modulatory role in the differential anxiogenic response to stress among males and females.