N-acetylcysteine (NAC) alleviates the peripheral neuropathy associated with liver cirrhosis via modulation of neural MEG3/PAR2/ NF-Ò¡B axis.

BACKGROUND AND AIM: Oxidative stress (OS) is accused in pathogenesis of many diseases, including liver cirrhosis by many mechanisms. One of them is the disturbance of long non coding maternally expressed 3 (MEG3)/protease activated receptor 2 (PAR2) downstream pathway. We aimed to investigate the role of this axis in cirrhotic neuropathy and whether an antioxidant compound such as N-acetylcysteine (NAC) could improve the peripheral nerve function through repression of MEG3/PAR2. METHODS: Thirty Wistar rats were used and divided into 5 groups; naive, thiacetamide (TAA) (200 mg/kg 3 times/week. i.p. for 8 weeks) and TAA+NAC (50 or 100 or 200 mg/kg/day) groups. Von Frey (VF) test for mechanical nociceptive responses, hepatic& neural MEG3, NF-Ò¡B and neural PAR2 expression by PCR, histological studies for liver and sciatic nerve together with the dorsopedal skin thickness were done. RESULTS: TAA induced significant decrease in liver function, negative VF test, an increase in the expression of hepatic& neural MEG3, NF-Ò¡B and neural PAR2. The histological studies showed cirrhotic changes with atrophy of the sciatic nerve and the dorsal skin. NAC improved the liver function together with reversal of the neural: functional, biochemical and histological changes in a dose dependent manner. CONCLUSIONS: NAC could improve the peripheral neuropathy in cirrhotic rat through suppression of MEG3/PAR2 expression.

Metformin potentiates cognitive and antidepressant effects of fluoxetine in rats exposed to chronic restraint stress and high fat diet: potential involvement of hippocampal c-Jun repression.

Several hypotheses link high fat diet (HFD) with the pathophysiology of depression and its response to antidepressants. This study aimed to determine the effect of metformin (MET) on the cognitive and antidepressant activity of fluoxetine (FLU) through its effect on c-Jun expression. Behavioral, cognitive function, biochemical, and histopathological studies were performed in non-HFD- and HFD-fed rats exposed to chronic restraint stress (CRS). Stressed group showed cognitive impairment, depressive-like symptoms, disturbed glucose homeostasis and lipid profile, reduced adiponectin level, brain-derived neurotrophic factor (BDNF) expression, and increased corticosterone and c-Jun. All these were aggravated by HFD. MET, FLU and their combination produced significant improvement in lipid profile with significant increase in adiponectin and BDNF expression. Corticosterone, body weight and insulin resistance showed significant decrease in the treated groups. Moreover, there was a significant decrease in hippocampal c Jun expression. There was a significant preferable effect toward the combination. Conclusion, MET may decrease the refractoriness to FLU and improves the cognition in individuals who are fed on HFD.