Protective effect of Toll-like receptor 4 antagonist on inflammation, EEG, and memory changes following febrile seizure in Wistar rats.

Neuroinflammation and fever are the main triggers in febrile seizures (FS). Focusing on inflammatory pathways and anti-inflammatory drugs could compensate for the limitations of existing medications. The aim of this study is to evaluate the neuroprotective effect of specific antagonizing Toll-like receptor 4 (TLR4), as a prominent inflammatory axis, on the consequences of FS and adulthood using animal models. Complex FS was induced on 9-11 day old male rat pups using a heated chamber. TAK-242, as a specific TLR4 inhibitor, was injected intraperitoneally before seizure induction. Seizure threshold, duration, and spike number were measured by electrocorticography. The levels of inflammatory cytokines, TLR4 protein expression, and oxidative stress markers were detected by enzyme-linked immunosorbent assay, western blotting, malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD) assessments in the cortex and hippocampus. Also, spatial and non-spatial memory were evaluated using the novel object recognition test (NORT) and double Y-maze test during adulthood. The results revealed that provoked inflammatory responses in neonate rats, after FS, were associated with the increase of the tumor necrosis factor alpha, interleukin-1ß, and enhanced TLR4 protein expression. Meanwhile, based on performed behavioral tests, the inflammatory process was also involved in adulthood memory deficit. Pretreatment with TAK-242 reduced the inflammatory cytokines and TLR4 protein expression in the cortex and hippocampus of neonate rats and improvement in memory deficit in NORT and double Y-maze tasks. Also, pretreatment with TAK-242 elevated seizure threshold, SOD, and CAT activities, and decreased seizure duration and MDA level with no significant change in spike number. TAK-242 possibly controlled FS via inhibiting inflammation.

Protective effects of M8­B, a TRPM8 antagonist, on febrile­ and pentylenetetrazol­induced seizures.

Epilepsy is a life­threatening disorder that is marked by recurrent seizures. Febrile seizure is a common neurological disorder observed in neonates. In many cases, reducing body temperature can prevent febrile seizure. Transient receptor potential cation channel subfamily M member 8 (TRPM8) is a cation channel that is involved in body thermoregulation. It was reported that M8­B, a TRPM8 antagonist, can reduce body temperature. Thus, we aimed to investigate the effect of M8­B on different experimental seizure models. Eight­day­old male Wistar rat pups were used for induction of febrile seizure. M8­B and diazepam were injected intraperitoneally. The rat pups were then transferred to a heated plexiglas chamber and the latency to the first febrile seizure was measured. In addition, different groups of mice were pretreated with M8­B and received a convulsant dose of pentylenetetrazol (PTZ). Latencies to stages 2 and 4 and duration of stage 5 seizure episodes were measured. Furthermore, the effect of M8­B on electroshock­induced seizures was also investigated and hindlimb extension time was measured. The results showed that M8­B decreased the body temperature of rat pups and increased the latency to the first febrile seizure, implying a significant protective effect. It also induced a significant anticonvulsant effect in PTZ ­ but not electroshock­induced convulsions. M8­B showed anticonvulsant effects in both febrile­ and PTZ­induced seizures. M8­B had a hypothermic effect with significant protective effects on febrile­ and PTZ­induced seizures; however, it did not produce similarly protective effects on seizures induced by electroshock.

Use of colchicine in cortical area 1 of the hippocampus impairs transmission of non-motivational information by the pyramidal cells.

Colchicine, a potent neurotoxin derived from plants, has been recently introduced as a degenerative toxin of small pyramidal cells in the cortical area 1 of the hippocampus (CA1). In this study, the effect of the alkaloid in CA1 on the behaviors in the conditioning task was measured. Injections of colchicine (1,5 µg/rat, intra-CA1) was performed in the male Wistar rats, while the animals were settled and cannulated in a stereotaxic apparatus. In the control group solely injection of saline (1 µl/rat, intra-CA1) was used. One week later, all the animals passed the saline conditioning task using a three-day schedule of an unbiased paradigm. They were administered saline (1 ml/kg, s.c.) twice a day throughout the conditioning phase. To evaluate the possible effects of cell injury by the toxin on the pyramidal cells, both the motivational signals while in the conditioning box and the non-motivational locomotive signs of the treated and control rats were measured. Based on the present study the alkaloid caused no change in the score of place conditioning, but affected both the sniffing and grooming behaviors in the group that received colchicine. However, the alkaloid did not show the significant effect on the rearing or compartment entering in the rats. According to the findings, the intra-CA1 injection of colchicine may impair the neuronal transmission of non-motivational information by the pyramidal cells in the dorsal hippocampus.