Neuroprotective effect of metformin in MPTP-induced Parkinson's disease in mice.

Metformin a well known antidiabetic drug has been recently investigated and proposed to promote neurogenesis and enhance the spatial memory formation. In the present study, we aim to investigate the neuroprotective effect of metformin with respect to Parkinson's disease (PD). MPTP (Sigma-Aldrich, St. Louis, MO, USA) (25mg/kg) along with Probenecid (250 mg/kg) was administrated for five consecutive days to induce Parkinsonism in mice. Metformin 500 mg/kg was administrated orally for 21 days. Motor co-ordination and locomotor activities were evaluated by rotarod and open-field tests. The oxidative stress levels were assessed by estimating the activity of superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT) and lipid peroxidation (LPO) specifically in the midbrain. Dopaminergic degeneration was evaluated by analyzing the tyrosine hydroxylase (TH) by immunostaining and nissl staining of the substantia nigra (SN) region of the brain. In addition brain-derived neurotrophic factor (BDNF) was also estimated. Our findings demonstrated that long-term metformin treatment resulted in significant improvement of the locomotor and muscular activities in MPTP-treated mice than acute treatment. Metformin treatment significantly improved the antioxidant activity as compared to MPTP-treated group. TH-positive cells decreased up to 16% in MPTP-treated mice as compared to normal mice (P<0.001) and were found to be protected from degeneration in metformin-treated mice (47%, P<0.01). Interestingly, BDNF levels were found to be significantly elevated in metformin treatment group as compared to MPTP treatment mice (P<0.001). In conclusion, metformin possesses neuroprotective activity and provides preclinical support for therapeutic prospective of this compound in the treatment of PD.

Effect of diazepam on neuromuscular transmission and its interaction with non-depolarizing muscle relaxants.

Neuromuscular blocking actions of diazepam and its interaction with some myoneural blocking agents were studied in dogs and in humans undergoing surgery under general anaesthesia. Diazepam alone had no effect on the response of tibialis anterior muscle to indirect stimulation in dogs. Again, diazepam in a bolus dose of 5 mg did not influence a pre-existing partial block by d-tubocurarine, gallamine or pancuronium. But a significant increase in both the degree and duration of block was observed when diazepam and d-tubocurarine were given simultaneously, suggesting an agonist action in diazepam. On the contrary, simultaneous use of diazepam and gallamine caused a significantly less intense block of tibialis muscle twitch tension as compared to gallamine alone, suggesting an antagonistic action. The degree and duration of block by d-tubocurarine were not affected significantly by simultaneous administration of diazepam in human beings. It is, therefore, concluded that diazepam in clinical doses can be safely used with d-tubocurarine in humans.

Diazepam prophylaxis for lignocaine induced convulsions.

The effectiveness of intraperitoneal phenobarbitone (4 mg/kg), pentobarbitone (6 mg/kg) and diazepam (2.5, 5 and 7.5 mg/kg) in preventing lignocaine-induced seizures was studied in rats. Although the barbiturates exerted a marked depressant action on wakefulness and gait of the rats, they were still associated with a very high incidence of convulsions and deaths following 100 mg/kg intraperitoneal lignocaine hydrochloride. Diazepam, however, even in doses (2.5 and 5 mg/kg) which did not produce marked sedation was able to completely prevent convulsions. Mortality was not completely prevented as one animal in each of the groups receiving these doses died without convulsing. Diazepam in the dose of 7.5 mg/kg completely prevented the seizures as well as the mortality but exerted a more profound effect on wakefulness and gait of the animals. The effectiveness of diazepam pretreatment in preventing lignocaine-induced seizures in rats is confirmed.