Modulation of sphingosine-1-phosphate receptor ameliorates harmaline-induced essential tremor in rat.

Essential tremor (ET) is one of the most common movement disorders with unknown etiology. Despite lack of effective clinical treatments, some potential therapeutic factors and modulation of some neurotransmitters have been utilized to ameliorate motor symptoms in the animal models of tremor. In the current study, male Wistar rats (n=10 in each group) weighing 40-60g were divided into vehicle control groups (saline or DMSO), saline/DMSO+harmaline (30mg/kg, i.p.)+fingolimod (FTY720) (1mg/kg, i.p, 1h before harmaline injection) groups. Open field, rotarod, wire grip and foot print tests were used to evaluate motor function. The results demonstrated that administration of FTY720 can improve harmaline-induced tremor in rats. Moreover, FTY720 ameliorated gait disturbance. The results showed that FTY720 can recover step width, left and right step length; however, FTY720 failed to recover mobility duration. FTY720 also improved falling time and time spent in wire grip and rotarod, respectively. The current study provides the first evidence for the effectiveness of FTY720 on motor function in the harmaline model of ET. Furthermore, neuroprotective effects of FTY720 demonstrated in this study offer sphingosine-1-phosphate receptor (S1PR) modulators as a potential neuroprotective candidate against substance-induced tremor and a possible strategy for the treatment of patients with tremor.

Potential mechanisms involved in the anticonvulsant effect of walnut extract on pentylenetetrazole-induced seizure.

OBJECTIVE: It was the aim of this study to determine the potential effect of walnut kernel extract (WKE) on experimentally induced seizures in rats and to evaluate the role of benzodiazepines and ethosuximide (ESM) within these pathways. MATERIALS AND METHODS: Male Wistar rats were selected and divided into eight groups. Seizures were evoked by intravenous infusion of pentylenetetrazole (PTZ; 2 mg/ml/min). In combination with PTZ, animals were treated with vehicle or WKE (100 mg/kg i.p.), with or without cotreatment with either flumazenil (FMZ; 5 mg/kg i.p.), ESM (150 mg/kg i.p.) or diazepam (DPZ; 0.5 mg/kg i.p.). RESULTS: WKE administration significantly increased the PTZ dose needed to induce the first myoclonic jerk (13.09 ± 1.29 vs. 49.71 ± 12.03 mg/kg; p < 0.001), decreased the severity of seizure grades and reduced the mortality rate to 0%. FMZ did not significantly reduce the anticonvulsant effect of WKE. The combination of DPZ and WKE showed a synergic anticonvulsant effect, whereas ESM had no significant influence (p > 0.05) on the WKE effects. CONCLUSION: These findings indicated that WKE was effective at reducing seizure severity, at increasing the dose to the first myoclonic jerk and highly efficacious at preventing mortality, because 100% of animals were protected. It seems that this positive effect could apply through signaling pathways other than benzodiazepine-mediated γ-aminobutyric acid receptors and may at least in part be similar to ESM.

Differential modulatory actions of GABAA agonists on susceptibility to GABAA antagonists-induced seizures in morphine dependent rats: possible mechanisms in seizure propensity.

In order to clarify the mechanisms involved in the susceptibility to GABA(A) antagonists-induced seizures in morphine dependent rats, we investigated how GABA(A) agonists modulate this vulnerability. Seizures were induced to animals by infusion of GABA(A) antagonists: pentylenetetrazole (PTZ), picrotoxin (PIC) and bicuculline (BIC). GABA(A) agonists, muscimol (MUS) and 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridin-3-ol (THIP), were administered intravenous (i.v.) before antagonists. Morphine-dependence significantly decreased the PTZ threshold dose (19.16±1.89 versus 25.74±1.25mg/kg) while, it had no effect on PIC induced seizures. BIC doses for both threshold and tonic-clonic seizures induction were significantly lower in morphine dependent rats (0.10±0.01 and 0.12±0.02 versus 0.25±0.02 and 0.39±0.07mg/kg respectively). In morphine-dependence, although pre-treatment with MUS significantly increased the required dose of PTZ for seizures threshold, THIP significantly decreased the required dose of PTZ for tonic-clonic convulsion. Moreover, MUS pretreatment completely recovered the effect of morphine dependency on BIC seizure activity. The results suggest that the capability of GABA(A) agonists on modulation of propensity to seizures induced by different antagonists in morphine-dependence is dissimilar. Therefore, it seems that long-term morphine alters some properties of GABA system so that the responsive rate of GABA(A) receptors not only to its antagonists, but also to its agonists will change differently.