Alcohol abuse affects several neurological pathways and causes significant alterations in the brain. Abstention from alcohol causes only a marginal decrease in oxidative stress and neuro inflammation. Our previous studies had shown that an active metabolite of vitamin A, all trans retinoic acid (ATRA), ameliorates alcohol induced toxicity. Hence in the present study we investigated whether ATRA regressed alcohol induced neuroinflammation. We focused on the role of silent mating type information regulation 2 homolog 1(SIRT1) and nuclear factor kappa-B (NFκB). Animals were administered with ethanol at a daily dose of (4 g/kg body weight) for 90 days. On the 91st day ethanol administration was stopped and animals were divided into ethanol abstention (A) and ATRA supplementation group (ATRA + A) (100 µg/kg body weight) and maintained for 30 days. Ethanol exposure increased markers of oxidative stress, inflammation and the activities of alcohol and acetaldehyde dehydrogenases and reduced the expression of SIRT1 in the whole brain.The ethanol induced altered expressions of NFκB and SIRT1 were modulated by supplementation of ATRA. Abstention also reduced toxicity, but to a lower extent in comparison with supplementation of ATRA. Our results seemed to suggest that ATRA regressed the mediators of ethanol induced neuroinflammation by reducing oxidative stress and by regulating the expression of NFκB and SIRT1. The ameliorative potential of ATRA was much higher than abstention.

Alcohol abuse affects several neurological pathways and causes significant alterations in the brain. Abstention from alcohol is an effective intervention against alcohol related diseases. But the recovery of the damaged cells to normal presents a major problem in those who have stopped alcohol consumption. Hence therapeutic interventions are needed. Our previous studies have shown that all trans retinoic acid (ATRA) is effective in reducing alcohol induced neuro toxicity. Chronic alcohol administration up-regulates and activates the NLRP3 inflammasome leading to caspase-1 activation and IL-1β production causing neuroinflammation. Hence, we investigated whether ATRA has any impact on NLRP3 inflammasomes activation. Rats were divided into two groups and were maintained for 90 days as control and ethanol group (4 ​g/kg body weight). After 90 days, ethanol administration was stopped and animals in the control group were divided into control and control ​+ ​ATRA (100 ​μg/kg body weight per day) groups; those in the ethanol group as ethanol abstention and ATRA (100 ​μg/kg body weight per day) and maintained for 30 days. Administration of ATRA reduced reactive oxygen species and endotoxins which were elevated in alcoholic rats. There was also reduction in the expression of NLRP3 inflammasome and caspase 1. Our results suggested ATRA down regulated NLRP3 activation with concomitant decrease in the release of caspase −1 and production of IL1β. However, all these parameters were higher in abstention in comparison with ATRA supplemented group. In short therapeutic intervention with ATRA regressed alcohol induced inflammasome activation better than abstention.

ATRA had better efficacy than just abstention in reducing ethanol-induced toxicity. The mechanism might be downregulation of CYP2E1, leading to reduced oxidative stress in the hepatocytes and thus impeding NFκB activation, cytokine production, activation of HSC and resulting in the reduction of inflammation and remodelling of fibrosis by modulating MMP and TIMP.

The therapeutic effect of melatonin (MEL) against aluminum (Al)-induced neurotoxicity was investigated in mouse cerebellum. Two groups of male albino mice were intraperitoneally injected with Al acetate or MEL alone, at doses of 3.5 or 7 mg kg À1 day À1 , respectively, for 6 weeks. During this period, another group of animals received a combination of both Al and MEL (3.5 þ 7 mg kg À1 day À1 ). At the end of the treatment cerebellum was removed and processed to examine the oxidative stress markers: superoxide dismutase (SOD), catalase (CAT), and thiobarbituric acid-reactive substances (TBA-RS). Oxidative stress increased significantly with administration of Al which was estimated by increased TBA-RS and reduction in the activities of SOD and CAT. However, these alterations were significantly reversed significantly following MEL treatment which was observed in co-administered group. Protective effects of MEL were also observed at electron microscopic level. Ultrastructural studies revealed an increase in vacuolization, chromatin condensation within the nucleus, degenerated purkinje cell, degenerated axon and degenerated granule cells in the cerebellum of Al-treated mice group whereas concurrent administration of MEL with Al reduced these changes. The results of the present investigation emphasize the potential use of MEL as a supplement in therapy of free radical based neurological disorders in which oxidative stress is involved.

Background To correlate serum and salivary phenytoin drug metabolite levels in males to phenytoin influenced gingival overgrowth (PIGO). Methods Thirty male patients who are to start with oral phenytoin therapy were recruited. Plaque index (PI), Gingival index (GI), and Oral hygiene index (OHI) were recorded. Basic periodontal therapy was performed. Patients were followed up at 3, 6, 9 and 12 months intervals. Based on the gingival status they were divided in to two groups; Group1 (responders) and Group 2 (non responders). Serum and Salivary samples were analyzed for the drug metabolite levels spectophotometrically. Results The mean values of phenytoin drug metabolite levels in serum of group 1 and group 2 subjects were 14.5 ± 2.6 μg/ml and 14.2 ± 1.7 μg/ml respectively, with p value of 0.66. The corresponding mean values of phenytoin drug metabolite levels saliva were 1.42 ± 0.34 μg/ml and 1.38 ± 0.37 μg/ml with p value of 0.75. Correlation of phenytoin drug metabolite to PI, GI, and OHI in both the groups did not show any statistical significance. (R values ranging from −0.229 to 0.434). Correlation between the serum and salivary drug metabolites in both the responder and non responder group also did not show any statistically significant relationship. Conclusion No correlation between the drug concentration in either the serum or saliva can be correlated to PIGO. Whole Saliva could be a useful tool in therapeutic drug monitoring of phenytoin. Clinical relevance Scientific rationale: To assess and compare the drug metabolite levels in serum and saliva of a neurologic condition where therapeutic drug concentration is of key importance to minimize the side effects. Principle finding: Saliva could be as useful as serum in deciding the drug concentration of phenytoin. And PIGO is not related drug concentrations. Practical implication: Monitoring the drug dosage is of paramount importance for the success of antiepileptic therapy as well as control of its side effects. This longitudinal study confirms that saliva could be an effective alternative to serum for monitoring drug dosage of phenytoin.