Anxiogenic and anxiolytic effects of memantine injected into the ventral hippocampus in male stressed mice.

OBJECTIVES: The effects of intra-ventral hippocampal memantine administration in male NMRI stressed mice were studied. METHODS: Two stainless steel gauge 23 guide cannulas were placed in the middle part of the mice ventral hippocampus using stereotaxic coordination. Seven days later, the animals were undergone to the stress protocol as follows: They experience four consecutive electro-foot shock stress sessions lasting for 10 min. Five or 30 min before each stress session, the animals received intra-ventral hippocampal (0.1, 1 and, 5 µg/mouse) or intraperitoneal (1, 5, and 10 mg/kg) memantine respectively. Eight days after stress termination, the animals were tested either for the maintenance of either anxiety (elevated plus maze) or depression (forced swimming test). RESULTS: Animals show anxiety eight days after stress termination. Intra-ventral hippocampal infusion of memantine (5 µg/mouse) 5 min before stress inhibited the anxiety-like behaviors. However, other doses of the drug exacerbate the stress effect. The drug, when injected peripherally exacerbated the stress effect in all doses. The drug by itself had no effect. In addition, animals also show depression nine days after stress termination and memantine (0.1, 1, and 5 µg/mouse) reduced the stress effect. The drug (0.1 µg/mouse) by itself induced depression in the animals. However, the drug when injected peripherally reduced the stress effect in all doses. CONCLUSIONS: It could be concluded that NMDA glutamate receptors in the ventral hippocampus may play a pivotal role in the mediation of maintenance of anxiety and depression induced by stress in the mice.

Ameliorating impacts of ginseng on the apoptosis of spermatogenic cells and sperm quality in temporal lobe epilepsy rat model treated with valproate.

Both epilepsy and valproate (VPA), as an antiepileptic drug, negatively affect male sexual function. The present study was conducted to evaluate the ameliorating impacts of ginseng on sperm quality, architecture of seminiferous epithelium and spermatogenic cell apoptosis in temporal lobe epilepsy (TLE) animal model treated with VPA. Fifty-six adult male rats were divided into seven groups including untreated control (Co), epilepsy (E), valproate (V), epilepsy-valproate (EV), epilepsy-ginseng (EG), valproate-ginseng (VG) and epilepsy-valproate-ginseng (EVG). Animals received daily intraperitoneal injections of valproate and ginseng for 30 days. We observed a significant decline in bilateral testes' weight and sperm counts, along with reduction in normal morphology in the EV group. Ginseng sharply improved both sperm counts and spermatozoa with normal morphology in EVG animals. Although sperm motility decreased in V and EV groups, ginseng ameliorated sperm motility in VG and EVG animals. Besides, VPA sharply decreased spermatogenesis quality and increased germ cell apoptosis. Finally, ginseng significantly diminished apoptosis in VG rats and improved spermatogenesis in both VG and EVG groups. In conclusion, ginseng treatment has shown a positive impact on spermatogenesis and sperm quality in TLE rats treated with VPA. Therefore, it may be a beneficial adjuvant along with VPA treatment in the epileptic patient.

Neuroprotective effects of lovastatin in the pilocarpine rat model of epilepsy according to the expression of neurotrophic factors.

Studies have suggested that neurotrophic factors (NTFs) are involved in the status epilepticus development. This indicates their essential role in mediating acquired epileptic conditions. Therefore, modulating the expression of NTFs may inhibit seizure-induced cell loss in the epileptic lesions. In this study, we examined the anti-apoptotic, anti-necrotic and regulatory effects of lovastatin on the expression of NTFs in the pilocarpine rat model of temporal lobe epilepsy (TLE). A total of 32 male Wistar rats were divided into 4 groups (n = 8 per group): i) normal; ii) non-treated epileptic group [intraperitoneal (i.p.) administration of 350-400 mg/kg pilocarpine]; iii) treatment group (pilocarpine-treated rats treated followed by 5 mg/kg lovastatin); and iv) vehicle epileptic rats treated with Carboxymethyl cellulose (CMC). Animals that had a behavioral score of 4-5 according to the Racine scale were selected for study participation. Three days after the first seizure, pilocarpine-treated rats received i.p. injections of lovastatin for 14 days. The rats were killed and prepared for histopathologic analysis as well as real-time RT-PCR 17 days after the first seizure. The results of this study showed increased mRNA expression of glial cell line-derived neurotrophic factor (GDNF) and Ciliary neurotrophic factor (CNTF) and decreased expressions of Brain-derived neurotrophic factor (BDNF), Neurotrophin-3 (NT-3), and Neurotrophin-4 (NT-4) mRNA in the epileptic rats treated with lovastatin. Histological analysis of neurodegeneration in the brain sections showed that the number of hippocampal apoptotic and necrotic cells significantly decreased in the treatment groups. Furthermore, numerical density of neurons per area was significantly higher in the treated groups compared with the untreated groups. Collectively, the results of this study have shown that lovastatin could attenuate seizure-induced expression of neurotrophic factors and consequently reduce hippocampal cell death in the pilocarpine rat model of TLE.

Modulation of axonal sprouting along rostro-caudal axis of dorsal hippocampus and no neuronal survival in parahippocampal cortices by long-term post-lesion melatonin administration in lithium-pilocarpine model of temporal lobe epilepsy.

Feature outcome of hippocampus and extra-hippocampal cortices was evaluated in melatonin treated lithium-pilocarpine epileptic rats during early and chronic phases of temporal lobe epilepsy (TLE). After status epilepticus (SE) induction, 5 and 20 mg/kg melatonin were administered for 14 days or 60 days. All animals were killed 60 days post SE induction and the histological features of the rosrto-caudal axis of the dorsal hippocampus, piriform and entorhinal cortices were evaluated utilizing Nissl, Timm, and synapsin I immunoflorescent staining. Melatonin (20 mg/kg) effect on CA1 and CA3 neurons showed a region-specific pattern along the rostro-caudal axis of the dorsal hippocampus. The number of counted granular cells by melatonin (20 mg/kg) treatment increased along the rostro-caudal axis of the dorsal hippocampus in comparison to the untreated epileptic group. The density of Timm granules in the inner molecular layer of the dentate gyrus decreased significantly in all melatonin treated groups in comparison to the untreated epileptic animals. The increased density of synapsin I immunoreactivity in the outer molecular layer of the dentate gyrus of untreated epileptic rats showed a profound decrease following melatonin treatment. There was no neuronal protection in the piriform and entorhinal cortices whatever the melatonin treatment. Long-term melatonin administration as a co-adjuvant probably could reduce the post-lesion histological consequences of TLE in a region-specific pattern along the rostro-caudal axis of the dorsal hippocampus.

A fast model of voltage-dependent NMDA receptors.

NMDA receptors are among the crucial elements of central nervous system models. Recent studies show that both conductance and kinetics of these receptors are changing voltage-dependently in some parts of the brain. Therefore, several models have been introduced to simulate their current. However, on the one hand, kinetic models-which are able to simulate these voltage-dependent phenomena-are computationally expensive for modeling of large neural networks. On the other hand, classic exponential models, which are computationally less expensive, are not able to simulate the voltage-dependency of these receptors, accurately. In this study, we have modified these classic models to endow them with the voltage-dependent conductance and time constants. Temperature sensitivity and desensitization of these receptors are also taken into account. We show that, it is possible to simulate the most important physiological aspects of NMDA receptor's behavior using only three to four differential equations, which is significantly smaller than the previous kinetic models. Consequently, it seems that our model is both fast and physiologically plausible and therefore is a suitable candidate for the modeling of large neural networks.

Effect of GABA(A) Receptors in the Rostral Ventrolateral Medulla on Cardiovascular Response to the Activation of the Bed Nucleus of the Stria Terminalis in Female Ovariectomized Rats.

BACKGROUND: The areas of the bed nucleus of the stria terminalis (BST) with a high density of estrogen receptors are involved in cardiovascular regulation and send axonal projections to the rostroventrolateral medulla (RVLM). We aimed to find the contribution of the RVLM to cardiovascular responses elicited by glutamate microinjection into the BST. METHODS: Experiments were done in α-chloralose anesthetized ovariectomized (OVX) or OVX estrogen treated (OVX+E) female Wistar rats. Drugs were microinjected into the BST and RVLM. The average changes in mean arterial pressure (MAP) and heart rate (HR) were compared between the case and control groups using t test and with the pre-injection values using paired t test. RESULTS: Unilateral microinjection of glutamate (0.25 M/50 nl) into the BST decreased MAP and HR, in the OVX+E and OVX rats. These cardiovascular responses were reversibly attenuated 10 minutes after microinjection of synaptic blocker cobalt chloride (CoCl(2), 5 mM/50 nl) into the ipsilateral RVLM. Re-stimulation of the BST 60 min after CoCl(2) injection elicited cardiovascular responses that were not different from the control values. Ipsilateral microinjection of GABA(A) antagonist bicuculline (1.0 mM/50 nl) into the RVLM caused a 50% attenuation of glutamate induced depressor and bradycardic responses in both groups. Ipsilateral microinjection of GABA(B) antagonist, phaclophen (5.0 mM/50 nl), into the RVLM did not affect the depressor and bradycardic responses due to re-stimulation of the BST by glutamate. CONCLUSION: The RVLM sympathetic premotor neurons contain GABA(A) receptors that mediate in part the sympathoinhibitory responses to stimulation of the BST in the OVX animals.