S-Nitrosoglutathione Attenuates Oxidative Stress and Improves Retention Memory Dysfunctions in Intra-Cerebroventricular-Streptozotocin Rat Model of Sporadic Alzheimer's Disease via Activation of BDNF and Nuclear Factor Erythroid 2-Related Factor-2 Antioxidant Signaling Pathway.

INTRODUCTION: The brain-derived neurotrophic factor (BDNF) and transcription nuclear factor erythroid 2-related factor-2 (NRF-2) play an important role in Alzheimer's disease (AD). However, the interactive involvement of BDNF and NRF-2 in respect to antioxidant mechanisms in different parts of the AD brain is still unclear. Considering the above condition, used S-nitrosoglutathione (GSNO) to examine whether it modulates the BDNF and NRF-2 levels to activate signaling pathway to promote antioxidant levels in AD brains. METHOD: AD was induced by intracerebroventricular infusion of streptozotocin (ICV-STZ, 3 mg/kg) in Wistar rats. The effect of GSNO was analyzed by evaluating the retention of memory in months 1, 2, and 3. After the behavior study, rats were sacrificed and accessed the amyloid beta (Aß)-40, Aß42, glutathione (GSH), BDNF, and NRF-2 levels in the hippocampus, cortex, and amygdala tissue. RESULTS: Pretreatment with GSNO (50 µg/kg/intraperitoneal/day) restored the BDNF, and NRF-2 levels toward normalcy as compared with ICV-STZ + saline-treated animals. Also, GSNO treatment reversed the oxidative stress and increased the GSH levels toward normal levels. Further, reduced Aß levels and neuronal loss in different brain regions. As a result, GSNO treatment improved the cognitive deficits in ICV-STZ-treated rats. CONCLUSION: The results showed that endogenous nitric oxide donor GSNO improved the cognitive deficits and ICV-STZ-induced AD pathological conditions, possibly via attenuating the oxidative stress. Hence, the above finding supported that GSNO treatment may activate BDNF and NRF-2 antioxidant signaling pathways in the AD brain to normalize oxidative stress, which is the main causative factor for ICV-STZ-induced AD pathogenesis.

Periostin: A Potential Biomarker and Therapeutic Target in Pulmonary Diseases.

Periostin is a matricellular, nonstructural protein belonging to the fasciclin family and is encoded by the POSTN gene in humans. Periostin plays an important role in maintaining a normal tissue matrix in the lungs. Despite the vital role as a structural mediator in tissue growth and repair, periostin is involved in the pathogenic mechanism during tissue remodeling and fibrosis. Periostin is a chemoattractant mediator, promotes eosinophil recruitment and adhesion on the airways sub-epithelial membrane of asthmatic patients. POSTN gene was identified as one of the highly expressed genes induced by interleukins IL-13, IL-5 and IL-4 - the key cytokines of Th2 immune responses in the bronchial tissues of asthmatic patients. This review highlights the potential role of periostin as a validated biomarker in respiratory disease progression and its candidacy to predict the response to treatments targeting Th-2 cytokines in bronchial asthma. In addition, its potential role in COPD, IPF, lung cancer and lung infection, is also speculated.   Keywords Periostin, Asthma, Pneumonia, COPD, Idiopathic pulmonary fibrosis, Biomarker.

S-nitrosoglutathione modulates HDAC2 and BDNF levels in the brain and improves cognitive deficits in experimental model of Alzheimer's disease in rats.

AIM: Alzheimer's disease (AD) is a neurodegenerative disorder which is characterized by cognitive deficits and abnormal memory formation. Histone acetylation is essential for hippocampal memory formation and improving the cognitive deficits, and histone deacetylase 2 (HDAC2) is increased in the hippocampus of AD patients. The present study evaluated the effects of the nitric oxide (NO) mimetics, L-arginine and the nitrosothiol NO donor, s-nitrosoglutathione (GSNO), on memory and brain HDAC2 levels in experimental animal model of sporadic Alzheimer's disease (sAD). METHODS: AD was induced experimentally in rats by intracerebroventricular injection of streptozotocin (STZ, 3 mg/kg). The effects of NO mimetics, GSNO and L-arginine, were assessed on STZ induced cognitive deficits in the Morris water maze (MWM) test, and, following this, the hippocampal homogenates were assayed for amyloid-ß, brain derived neurotropic factor (BDNF) and HDAC2 levels. The neurobehavioral and biochemical data of the drug treated groups were compared with those of experimental control group. RESULTS: The results showed that icv-STZ induced cognitive deficits were differentially attenuated by GSNO (50 µg/kg) and, to a lesser extent, L-arginine (100 mg/kg) with improvement in the spatial learning tasks in MWM test. These behavioral changes were associated with decreased levels of biochemical markers viz. amyloid ß, BDNF and HDAC2 levels in hippocampus. CONCLUSIONS: It is inferred that NO donors like GSNO could influence AD pathophysiology via epigenetic modification of HDAC2 inhibition.

Pharmacological and biochemical studies on the protective effects of melatonin during stress-induced behavioral and immunological changes in relation to oxidative stress in rats.

Stress is known to precipitate neuropsychiatric diseases, and depending upon its nature and intensity it can also influence the functioning of the immune system. Melatonin (N-acetyl-5-methoxy tryptamine) a pineal gland hormone and potent antioxidant is known to protect against many diseases. Effect of melatonin in stress-induced neuro-immunomodulation is not well elucidated. Therefore in the present study, the protective effects of melatonin were evaluated in restraint stress (RS)-induced behavioral and immunological changes in rats. RS for 1 h significantly reduces (i) percentage of open-arm entries and (ii) percentage of time spent on open-arm in elevated plus maze (EPM) test parameters (p < 0.01) and significant increase in MDA levels in brain homogenate when compared to non-RS control groups (p < 0.05). In immunological studies, both humoral and cell-mediated immune responses to antigen were significantly suppressed by RS for 1 h for 5 consecutive days, as evidenced by significant reduction in (i) anti-SRBC antibody titre, (ii) PFC counts, (iii) percentage change in paw volume, and (iv) Th1 (IFN-γ) and Th2 (IL-4) cytokine levels (p < 0.001 in all parameters). These RS-induced immunological changes were associated with significantly increased lipid peroxidation (MDA) levels in serum and significantly decreased activity of (i) SOD, (ii) CAT, and (iii) GSH levels in RS (X5)-exposed group (p < 0.02). Pretreatment with melatonin (10, 50, and 100 mg/kg) significantly reversed these RS-induced changes in EPM test parameters and humoral and cell-mediated immunological parameters, as well as oxidative stress markers in a dose-dependent manner by differential degrees (p < 0.001). Results are strongly suggestive of the involvement of free radicals during stress-induced neurobehavioral and immunological changes. These changes were significantly restored by melatonin pretreatment. We can conclude that melatonin may have a protective role during such stress-induced neuro-immunomodulation.

Cellular and molecular mechanisms of action of polyherbal preparation UNIM-352 in experimental models of bronchial asthma.

Bronchial asthma is a chronic inflammatory disorder of the airways and pharmacotherapy is dependent on anti-inflammatory and bronchodilator agents. However, adverse effects of these agents on chronic administration and sometimes non-responsiveness to these drugs have prompted the search for viable alternatives from medicinal plant sources. UNIM-352 is a polyherbal preparation traditionally used in the Unani system of Indian medicine for the treatment of bronchial asthma. The present study defines the possible cellular and molecular mechanisms of action of UNIM-352 in experimental models of bronchial asthma and validates the observed therapeutically beneficial effects. Wistar rats were immunized and challenged with ovalbumin, and blood and bronchoalveolar lavage (BAL) fluid were assayed for cytological and biochemical markers. UNIM-352 (200 and 400 mg/kg) markedly reduced the eosinophil and neutrophil counts in both blood and BAL compared to control. The polyherbal agent also attenuated the levels of TNF-α, IL-4, GM-CSF and NF-κB whereas histone deacetylase (HDAC) levels were elevated, in both blood and BAL fluid. All effects of UNIM-352 were comparable with the standard drug, prednisolone. The results demonstrated possible cellular and molecular mechanisms of UNIM-352 and thus explain its beneficial effects in bronchial asthma.

Differential neuromodulatory role of NO in anxiety and seizures: an experimental study.

Nitric oxide is a simple, ubiquitous, diatomic molecule with complex neuromodulatory functions. Anxiety and seizures are closely similar neurobehavioral disorders and are regulated by limbic system. The present study evaluated the regulatory roles of NO in these pathophysiological states in experimental models. In test for anxiety, aminophylline induced anxiogenic responses were assessed by the elevated plus maze (EPM) test, and a low dose of the drug (50 mg/kg) reduced both open arm entries and open arm time in rats. Pretreatment with the NO mimetic, L-arginine (500 and 1000 mg/kg) and melatonin (50 mg/kg) attenuated aminophylline induced anxiogenesis whereas the NO synthase inhibitors, L-NAME and 7-NI (30 mg/kg) aggravated the anxiogeneic response. Such aminophylline induced neurobehavioral suppression in the EPM activity was accompanied by increases in MDA levels and reductions in GSH and NOx activity in brain homogenates - changes which were reversed by L-arginine and melatonin pretreatments. In tests for seizures, aminophylline induced seizures and mortality at higher dose levels of the drug (300 mg/kg). Interestingly, such seizures and mortality in rats were antagonized by L-NAME and 7-NI pretreatments. On the other hand, L-arginine tended to potentiate seizures after sub-convulsive dose (100 mg/kg) of this methylxanthine. Aminophylline induced seizures were accompanied by greater elevations in brain MDA levels, whereas, GSH levels were consistently lowered. Unlike that seen during anxiety, NOx levels were increased in brain homogenates of these rats. The changes in oxidative stress markers were neutralized by NO synthase inhibitors. Synergistic anticonvulsant effect on aminophylline seizures was seen when L-NAME was combined with melatonin. These pharmacological and biochemical data indicate that aminophylline induced anxiety and seizures are differentially modulated by NO.

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.

Amelioration by Withania somnifera of neurobehavioural and immunological markers in time dependent sensitization induced post traumatic stress disorder in rats.

AIMS AND OBJECTIVES: Posttraumatic stress disorder (PTSD) is a complex neuropsychiatric pathophysiology with an unmet need for safe, effective, and sustainable therapeutic modalities. Thus, the present study evaluated the effects of Withaniasomnifera (WS, Ashwagandha) on an experimental model of PTSD in rats. MATERIALS AND METHODS: Wistar rats (200-250 g) were used and time-dependent sensitization (TDS) was used as the experimental model of PTSD. Standardized WS root extract (100 and 300 mg/kg, p.o. for 15 days) was administered with TDS and their effects were observed on neurobehavioral (anxiety) and brain cytokines, corticosterone, and oxidative stress markers. RESULTS: Exposure to TDS resulted in anxiogenic behavior in the elevated plus maze (EPM) test, i.e., reductions in open arm entries and open arm time, as compared to the control group. Pretreatment with WS extract (100 and 300 mg/kg × 14 days) attenuated the TDS-induced anxiogenic activity in a dose-related manner, and these WS effects were comparable to those seen after the comparator drug fluoxetine (10 mg/kg). Assay of brain homogenates showed that TDS also resulted in elevations in brain interleukin-6 and reduction in corticosterone levels in both the hippocampus and prefrontal cortex (PFC), which were reversed after WS pretreatments. Further, WS pretreatment also reversed the TDS-induced changes in brain oxidative stress markers, namely elevated malondialdehyde and reduced glutathione levels in both the hippocampus and PFC. CONCLUSION: These results suggest that WS could have potential as a therapeutic agent for treating PTSD by attenuating anxiogenesis, neuroimmune axis activation, and oxidative stress.

Modulation by Withania somnifera of stress-induced anxiogenesis and airway inflammation in rats.

OBJECTIVES: Stress is an aversive stimulus which disrupts the biological milieu of the organism and a variety of emotional and environmental stressors are known to influence allergic and immunological disorders like bronchial asthma but the pharmacological basis of such interactions is not clearly defined. Withania somnifera (ashwagandha) is a potent anti-stress agent used widely in Indian traditional medicine and the present experimental study evaluated the effects of W. somnifera extract (WSE) on chronic stress-induced neurobehavioral and immunological responses in an experimental model of allergic asthma in rats. METHODS: Wistar rats (200-250 g) were immunized and challenged with ovalbumin (OVA) and exposed to restraint stress (RS) and WSE treatments for 15 days. Following this, anxiety behavior was assessed by the elevated plus maze (EPM) test, and blood and BAL fluid samples were collected for measuring of inflammatory/immune markers by ELISA and biochemical assay. The data of the various treatment groups were analyzed by ANOVA and Tukey's test. RESULTS: Restraint stress (RS) induced anxiogenic behavior in the (EPM) test in OVA immunized rats, and this was attenuated by WSE (200 and 400 mg/kg), in a dose related manner. Examination of blood and BAL fluid in these RS exposed rats also resulted in elevations in IgE, TNF-α and IL-4 levels, which were also attenuated by WSE pretreatments. Further, WSE pretreatment neutralized the such RS induced changes in oxidative stress markers viz. elevated MDA and reduced GSH levels. CONCLUSIONS: The data pharmacologically validates role of stress in asthma and suggests that adaptogens like WSE could be a potential complementary agent for reducing anxiety as well as airway inflammation by a multi-targeted and holistic approach. The study also highlights the significance of integration of traditional and modern medical concepts in such chronic disorders.

Modulation of Immunological, Biochemical, and Histopathological Changes of Airway Remodeling by Withania somnifera in an Experimental Model of Allergic Asthma in Rats.

Objectives: Airway remodeling in asthma involves chronic inflammation associated with structural changes, which result in severe airflow limitation and very few therapeutic options. Thus, the present study was designed to experimentally evaluate the ameliorative effects of Withania somnifera (WS) root extract against Ovalbumin (OVA)-induced airway remodeling in a rat model of asthma. Methods: Wistar rats were immunized (i.p) and challenged (aerosol) with ovalbumin (OVA), and the effects of WS extract were investigated on the development and progress of airway remodeling by assessing immunological, biochemical, and histological changes in these rats. Results: OVA-immunization and challenge in rats resulted in significant increases in the levels of IL-13, 8-OhdG, TGF-ß, hydroxyproline, and periostin in bronchoalveolar lavage fluid (BALF) and serum/lung homogenate compared to normal control (saline only) rats, and these changes were attenuated after WS extract (200 and 400 mg/kg), as well as dexamethasone (DEX, 1 mg/kg) pretreatments. Further, WS extract attenuated histopathological changes and maintained lung integrity. In herb-drug interactions, sub-threshold doses of WS extract and DEX showed synergistic effects on all parameters studied as compared to either form of monotherapy. Conclusion: These results indicated that WS exerted significant protective effects against airway remodeling in the experimental model by modulating inflammatory and fibrotic cytokines, and could have the potential for developing a therapeutic alternative/adjunct for the treatment of airway remodeling of bronchial asthma.

Assessment of protective role of polyherbal preparation, Livina, against anti-tubercular drug induced liver dysfunction.

The present study evaluated the possible protective role of Livina (a polyherbal preparation) against anti-tubercular therapy (ATT)-induced liver dysfunction in patients of pulmonary tuberculosis. Patients were given intensive phase treatment with 4-drugs (rifampicin, INH, pyrazinamide and ethambutol) used for anti-tubercular therapy for 2 months, followed by a 4-month continuous phase treatment with 2 drugs (rifampicin and INH) under clinical advice and supervision. Both qualitative and quantitative measures of liver function were assessed, at different time intervals, before and after ATT. Analysis of data showed that the incidence of qualitative manifestations of liver dysfunction were greater in the placebo treated group as compared to the test drug group. None of the patients of either group showed clinical jaundice. Most signific changes ant were observed in the SGOT and SGPT levels in the placebo group, wherein the levels of both enzymes were higher at 4 and 8 weeks post-ATT, as compared to the respective baseline (0 week) values. When Livina (2 capsules twice daily) was given with ATT drugs, incidence of qualitative manifestation of liver dysfunction was insignificant and SGOT and SGPT levels were also significantly lower than the placebo+AITT drugs treated group. These results indicate that the test drug (Livina) was efficacious, against ATT-induced hepatic dysfunction in patients of pulmonary tuberculosis.

Effects of diesel exhaust, heavy metals and pesticides on various organ systems: possible mechanisms and strategies for prevention and treatment.

Environmental pollutants have a significant impact on the ecosystem and disrupt balance between environment, human and non-human components that result in deleterious effects to all forms of life. Identifying environmental factors for potential imbalance are extremely crucial for devising strategies for combating such toxic dysregulation. Automobile exhaust (in air), heavy metals (in food and water) and pesticides (in air, food, soil and water) are the most common environmental pollutants and their short and long-term exposures can cause hazardous effects in humans leading to systemic disorders involving lungs, kidney and immune systems. Mechanisms involved in genesis of such toxic effects have revealed complex, interactive pathways. Strategies for the protection of homeostasis and health, viz., general preventive measures, nutritional supplements and herbal agents have been described, to counter these pollutants induced damaging effects on various body systems.

Stress Gastric Ulcers and Cytoprotective Strategies: Perspectives and Trends.

Stress gastric ulceration is a clinical condition leading to morbidity/mortality and complex etiopathological factors are involved. Pharmacotherapy of such gastric mucosal lesions is not consistent and novel strategies are being explored. Targeting gastrointestinal factors have showed equivocal results and there is a possibility of involvement of extra-gastrointestinal factors. Stress is a highly interactive biological response in which the brain plays a key role. The involvement of brain substrates like the limbic system (amygdala, cortex, hippocampus) and behavioral traits has been investigated and research data has shown that the limbic brain-gut axis may be involved in the regulation of gastric mucosal integrity during stressful situations. The amygdaloid complex, its connections with other limbic structures and their neural networks act in tandem to contribute to both stress ulceration and gastroprotection. Complex neurotransmitter interactions in these areas involving biogenic amines and neuropeptides have been shown to modulate stress ulcerogenesis in experimental models. The immune system and brain-immune interactions also appear to play a decisive role in the genesis of such stress gastric lesions and the possibility of a brain-gut-immune axis has been proposed during stress gastric lesions. More recent studies have shown the involvement of oxidative stress and nitric oxide as well as their interactions during such stress gastric pathology, indicating the possible role of antioxidants and NO modulators as gastroprotective agents for stress ulceration. In view of the complex pathophysiology, multiple targets and lack of consistent therapeutic modalities, newer/alternative hypotheses are constantly emerging, which could be explored for effective treatment strategies aimed at gastric cytoprotection. Herbal agents with adaptogenic properties could be worth exploring in this regard as some of these phytopharmaceutical agents used in traditional medicine have been shown to exhibit gastric cytoprotection as part of their anti-stress profile. Further, their interactions with brain neurotransmitters and immune mechanisms and their relative safety could make them prospective leads for stress ulcer prophylaxis and treatment.

Alzheimer's Disease: A Contextual Link with Nitric Oxide Synthase.

Nitric oxide (NO) is a gasotransmitter with pleiotropic effects which has made a great impact on biology and medicine. A multidimensional neuromodulatory role of NO has been shown in the brain with specific reference to neurodegenerative disorders like Alzheimer's disease (AD) and cognitive dysfunction. It has been found that NO/cGMP signalling pathway has an important role in learning and memory. Initially, it was considered that indirectly NO exerted neurotoxicity in AD via glutamatergic excitotoxicity. However, considering the early development of cognitive functions involved in the learning memory process including long term potentiation and synaptic plasticity, NO has a crucial role. Increasing evidence uncovered the above facts that isoforms of NOS viz endothelial NO synthase (eNOS), neuronal NO synthase (nNOS) and inducible NO synthase (iNOS) having a variable expression in AD are mainly responsible for learning and memory activities. In this review, we focus on the role of NOS isoforms in AD parallel to NO. Further, this review provides convergent evidence that NO could provide a therapeutic avenue in AD via modulation of the relevant NOS expression.

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.

Protective effects of different antioxidants against endosulfan-induced oxidative stress and immunotoxicity in albino rats.

Endosulfan exposure (8 and 16 mg/kg) to rats significantly decreased the activities of superoxide dismutase and catalase, level of reduced glutathione and increased lipid peroxidation. The primary and secondary antiSRBC antibody titers, plaque forming cells counts and delayed hypersensivity reaction, and the TH1 or TH2 cytokines levels were significantly suppressed in a dose dependent manner. L-ascorbic acid and alpha-tocopherol produced a synergistic reversal of oxidative stress parameters following endosulfan exposure. N-acetylcysteine produced significant reversal of altered oxidative stress parameters and immune response after endosulfan exposure. A significant attenuation of the oxidative stress markers and immunotoxicity with a combined therapy of L-ascorbic acid plus alpha-tocopherol and with N-acetylcysteine was clearly demonstrated by the present results.

Inhibitory effects of sildenafil and tadalafil on inflammation, oxidative stress and nitrosative stress in animal model of bronchial asthma.

BACKGROUND: Cyclic neucleotides are involved in many cellular functions including smooth muscle relaxation, inflammation, and signal transduction. Sildenafil and tadalafil are phosphodiesterase-5 (PDE-5) inhibitors which prevent the degradation of cyclic neucleotide i.e. guanosine 3',5' cyclic monophosphate (cGMP) and increase the levels of cGMP. In this study sildenafil and tadalafil were evaluated for their anti-inflammatory, anti-oxidative and anti-nitrosative stress potential in animal model of bronchial asthma. METHODS: Wistar rats were sensitized with 10 mg intraperitoneal (ip) ovalbumin adsorbed to 10 µg of aluminum hydroxide on day 0. Animals were given sildenafil (1 and 3 mg/kg ip) and tadalafil (1 and 3 mg/kg ip) from day 1 to day 14. Also, on day 14 animals were challenged with ovalbumin (1 mg ip). After 24 h, samples were collected to analyze interleukin-4 (IL-4) and tumour necrosis factor-α (TNF-α), in serum and bronchoalveolar lavage fluid (BALF). The oxidative stress markers malondialdehyde (MDA), reduced glutathione (GSH) and nitric oxide metabolites (NOx) were also measured in serum. RESULTS: Pre-treatment with sildenafil (1 and 3 mg/kg ip) and tadalafil (1 and 3 mg/kg ip) significantly reduced the levels of pro-inflammatory cytokines IL-4 and TNF-α in rat serum and BALF. In addition, pre-treatment with both the drugs decreased the levels of MDA and NOx and increased the levels of GSH in serum. CONCLUSIONS: Sildenafil and tadalafil decreased pro-inflammatory cytokines in serum and BALF. Both drugs inhibit oxidative and nitrosative stress in animal model of bronchial asthma and could have a therapeutic potential in bronchial asthma.

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.

Amelioration by nitric oxide (NO) mimetics on neurobehavioral and biochemical changes in experimental model of Alzheimer's disease in rats.

The present study evaluated the effects of s-nitrosoglutathione (GSNO), a nitrosothiol and sustained NO releaser, on experimental model of sporadic Alzheimer`s disease (sAD) in rats. Levels of Aß40, Aß42 and BDNF were assessed in brain hippocampal homogenates for correlative purposes. Intracerebroventricular-Streptozotocin (icv-STZ) induced increased escape latencies (acquisition) and reduced time in target quadrant (probe trial) in Morris Water Maze (MWM) test at 3 months post icv-STZ administration. These behavioural changes were associated with increased Aß depositions and lowered BDNF levels in brain hippocampal homogenates. Pre-treatment with GSNO (50 µg/kg/day), reduced the icv-STZ induced cognitive deficits in acquisition and probe trials in the MWM. The icv-STZ induced elevations in Aß40 and Aß42 and reduced levels of BDNF in hippocampal homogenates were also attenuated after GSNO treatment in these rats. The NO-precursor, l-arginine (100 mg/kg) induced similar effects on behavioural and biochemical parameters tested but was marginally less consistent as compared to those seen with GSNO. The results suggest that GSNO ameliorates the cognitive deficits and associated brain biochemical changes in this experimental model of sporadic AD, and NO-BDNF interactions could play crucial role in these effects.

Recent studies on cellular and molecular mechanisms in Alzheimer's disease: focus on epigenetic factors and histone deacetylase.

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders mainly affecting elderly people. It is characterized by progressive loss of memory and cognitive function. More than 95% of AD cases are related to sporadic or late-onset AD (LOAD). The etiology of LOAD is still unclear. It has been reported that environmental factors and epigenetic alterations play a significant role in AD pathogenesis. Furthermore, recently, genome-wide association studies (GWAS) identified 10 novel risk genes: ABCA7, APOE, BIN1, CD2AP, CD33, CLU, CR1, MS4A6A, MS4A4E, and PICALM, which play an important role for LOAD. In this review, the therapeutic approaches of AD by epigenetic modifications have been discussed. Nowadays, HDAC inhibitors have clinically proven its activity for epigenetic modifications. Furthermore, we try to establish the relationship between HDAC inhibitors and above mentioned LOAD risk genes. Finally, we are hoping that this review may open new area of research for AD treatment.