Effect of Ursodeoxycholic Acid on Pentylenetetrazole Kindling and Kindling Induced Memory Impairment in Rat

BACKGROUND AND OBJECTIVE: Epilepsy is one of the common diseases of the brain that about 30-40% of patients with epilepsy experience recurent attacks due to drug resistance. Recently, the beneficial effects of Ursodeoxycholic acid on brain disorders have been considered. The aim of this study was to evaluate the effect of Ursodeoxycholic acid(UDCA)on the Pentylenetetrazole (PTZ) induced kindling, and related learning and memory impairments on Morris water maze. METHODS: This experimental study was done on 32 male Winstar rats divided into 4 groups. The first(n=7)and the second(n=9)groups have received three injections of 0.5 ml NaCl or 50 mg/kg of UDCA respectively and third(n=7) and fourth(n=9) groups have received fifteen injections of 0.5 ml NaCl or 50 mg/kg of UDCA respectively. All injections were given intraperitoneally(ip)(every 48 hours). In all groups, chemical kindling were started after third injections. Twenty-four hour after the last injection, spatial memory was investigated in the Morris water maze. FINDING: Fifteen injections of UDCA significantly reduced the seizure stage from 3.5±0.17 to 3.08±0.11 and duration of stages five from 12.37±1.21 to 8.43±1.09 and increased time to reach the stage five seizures from 1021.65±72.07 to 1252.41±49.63 as compared to control group. However, three injections of UDCA have no effect on the kindling process. However, three time administration of UDCA significantly increased reference memory from 18.72±1.2 s to 26.11±1.8 s. CONCLUSION: Ursodeoxycholic acid inhibits chemical kindling and improves kindling induced memory impairment

Investigating the effect of enzymatic elimination of endocannabinoids inhibitors on tonic- colonic seizure provoked by PTZ

BACKGROUND AND OBJECTIVE: In recent years, numerous attempts were done to find new treatment methods for patients with drug-resistant epilepsy. Anandamide (Anandamides; AEA) and di-Arachidonoylglycerol (2-Arachidonoylglycerol; 2-AG) are two major ligands of endocannabinoid system can be produced or deleted by a certain enzymatic pathway. Given the frequency and significance of these endocannabinoid ligands, it seems that endocannabinoid system in the brain can be changed with pharmacologically manipulating in the pathway of these two main ligands. Therefore, the aim of this study was to evaluate the effect of enzymatic elimination of endocannabinoids inhibitors on tonic-clonic seizure caused by PTZ. METHODS: In this exprimental study 35 Adult male wistar rats were used in 4 groups. Tonic-colonic seizure was induced through single intra-peritoneal injection of PTZ (80 mg/Kg). Latency and duration of each five behavioral seizure stages were monitored for 30 minutes. To inhibit Anandamides elimination, URB and LY (URB: 1 mg/kg, LY: 2.5 mg/kg, i.p), to inhibit 2-2-Arachidonoylglycerol&nbsp;degradation WWL and JJKK (JJKK: 1 mg/kg, WWL: 5 mg/kg, i.p), were used, all dissolved in DMSO and injected 15 minutes before PTZ injection. In sham group, PTZ was injected after DMSO.Time and duration of all five behavioral stages of seizure were recorded for 30 minutes. FINDINGS: Delay to stages 4 and 5 in DMSO+PTZ group were 206+39 and 209+39, respectivly. While in JJKK+WWL+DMSO+PTZ group delay to stages 4 and 5 were 630+159 and 726+360, respectivly, which reveald significant increase (p<0.05). In addition, percentage of stage 5 incidence and mortality rate were 91% in DMSO+PTZ group, while both indexes were decreased to 50% in (JJKK+WWL+DMSO) group. CONCLUSION: Contemporary using both WWL and JJKK as inhibitors of 2-Arachidonoylglycerol elimination effectivly reduced tonic- clonic seizure

A Study on the Effects of Orally Administered Copper Sulfate on Learning ‎and Spatial Memory of Wistar Rats

BACKGROUND AND OBJECTIVE: Copper is one of the main micronutrients in the human body. Malfunction in copper homeostasis results in Menkes syndrome and Wilson’s disease, which are associated with complications such as seizure and impairments in learning and memory. Use of high copper concentrations can cause permanent damage to the cells and neurons. The aim of this study was to examine the toxic effects of orally administered copper sulfate on rats’ learning in Morris water maze. METHODS: In this experimental study, 39 Wistar rats were divided into male (n=21) and female (n=18) groups. These two groups were each randomly divided into three sub-groups. The control group received distilled water, while the other two groups were administrated 1 and 1.5 mM of copper sulfate, dissolved in distilled water for a period of one month. After this period, the Morris water maze was incorporated to evaluate the spatial memory of rats. FINDINGS: In male rats, copper sulfate, which was added to drinking water, made no significant changes in the distance traveled to find the platform (24.09%±3.01 in the control group, 26.06%±2.95 in the 1 mm copper sulfate group, and 25.68%±1.82 in the 1.5 mM copper sulfate group), the time spent to find the platform (23.93±2.87 in the control group, 25.54±3.47 in the 1 mM copper sulfate group, and 25.33±1.92 in the 1.5 mM copper sulfate group), or the swimming speed. The comparison of female groups showed that 1 and 1.5 mM concentrations of copper sulfate could not cause any significant impairments in learning of rats. CONCLUSION: The results showed that the addition of copper sulfate to drinking water have no detrimental impacts on the memory or learning of male and female rats

Effect of intraperitoneal injection of clozapine on pentylenetetrazole-kindled rats

Background: Clozapine is one of the atypical antipsychotic drugs that is efficacious in patients unresponsive to typical antipsychotics. There are controversial evidences on convulsive effects of clozapine. This study was carried out to assess the effect of clozapine on seizures pentylenetetrazole-induced kindling in Wistar rats.Materials and Methods: In this experimental research 40 Wistar rats were randomly assigned to five groups. For the induction of kindling, pentylenetetrazole (45 mg/kg, ip) was administrated to rats. Animals were kindled until all of them showed the fifth stage of seizure for three consecutive times. Forty-eight hours after the last injection of pentylenetetrazole, 5 different doses of clozapine were administrated in separate studies and the results were compared with previous recorded seizure parameters obtained from the same animals using One-way ANOVA and paired t-test.Results: The results showed that clozapine (1 mg/kg) has a proconvulsive effect, whereas in higher dose (7.5 mg/kg) it has an anticonvulsive effect on seizure parameters. Conclusion: Different doses of clozapine have different effects on seizure parameters and the discrepancy seen in human and animal reports may be due to the use of different doses of clozapine on pentylenetetrazole-induced kindling

BDNF modulates GABA(A) receptors microtransplanted from the human epileptic brain to Xenopus oocytes

Cell membranes isolated from brain tissues, obtained surgically from six patients afflicted with drug-resistant temporal lobe epilepsy and from one nonepileptic patient afflicted with a cerebral oligodendroglioma, were injected into frog oocytes. By using this approach, the oocytes acquire human GABA(A) receptors, and we have shown previously that the “epileptic receptors” (receptors transplanted from epileptic brains) display a marked run-down during repetitive applications of GABA. It was found that exposure to the neurotrophin BDNF increased the amplitude of the “GABA currents” (currents elicited by GABA) generated by the epileptic receptors and decreased their run-down; both events being blocked by K252A, a neurotrophin tyrosine kinase receptor B inhibitor. These effects of BDNF were not mimicked by nerve growth factor. In contrast, the GABA(A) receptors transplanted from the nonepileptic human hippocampal uncus (obtained during surgical resection as part of the nontumoral tissue from the oligodendroglioma margins) or receptors expressed by injecting rat recombinant α1β2γ2 GABA(A) receptor subunit cDNAs generated GABA currents whose time-course and run-down were not altered by BDNF. Loading the oocytes with the Ca(2+) chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetate-acetoxymethyl ester (BAPTA-AM), or treating them with Rp-8-Br-cAMP, an inhibitor of the cAMP-dependent PKA, did not alter the GABA currents. However, staurosporine (a broad spectrum PK inhibitor), bisindolylmaleimide I (a PKC inhibitor), and U73122 (a phospholipase C inhibitor) blocked the BDNF-induced effects on the epileptic GABA currents. Our results indicate that BDNF potentiates the epileptic GABA(A) currents and antagonizes their use-dependent run-down, thus strengthening GABAergic inhibition, probably by means of activation of tyrosine kinase receptor B receptors and of both PLC and PKC