Do sodium channel blockers have neuroprotective effect after onset of ischemic insult?

OBJECTIVE: Cerebral ischemia causes a series of pathophysiologic events that may result in cerebral infarct. Some neurons are more vulnerable to ischemia, particularly pyramidal neurons in the hippocampal CA1 region. Pharmacologic intervention for treatment of cerebral ischemia aims to counteract secondary neurotoxic events or to interrupt the progression of this process. In the present study, we compare the neuroprotective effects of sodium channel blockers (mexiletine, riluzole and phenytoin) and investigate whether they have neuroprotective effect when given after ischemic insult. METHODS: A transient global cerebral ischemia model was performed in this study by clipping bilateral common carotid arteries during 45 minutes. Riluzole (8 mg/kg), mexiletine (80 mg/kg) and phenytoin (200 mg/kg) were injected into the rats intraperitoneally 30 minutes before or after reperfusion. Lipid peroxidation levels and cerebral water contents were evaluated 24 hours after ischemia. Histopathologic assessment of hippocampal region was determined 7 days after ischemia. RESULTS: Riluzole, mexiletine and phenytoin treatment after global ischemia significantly decreased water content of the ischemic brain (p<0.05 for each). No significant difference was observed in cerebral edema among the drug treatment groups (p>0.05). When pre-treatment and post-treatment groups were compared with each other, only riluzole pre-treatment group revealed better result for cerebral edema (p<0.05). Pre-treatment with these drugs revealed significantly better results for the malonyldialdehyde (MDA) level and the number of survival neuron on the hippocampal region than the post-treatment groups. CONCLUSION: It is demonstrated that riluzole, mexiletine and phenytoin are potent neuroprotective agents in the rat model of transient global cerebral ischemia, but they are more effective when given before onset of the ischemia.

Neuroprotective effect of etomidate in the central nervous system of streptozotocin-induced diabetic rats.

It is well known that hyperglycaemia due to diabetes mellitus leads to oxidative stress in the central nervous system. Oxidative stress plays important role in the pathogenesis of neurodegenerative changes. In the present study we investigated the possible neuroprotective effect of etomidate against streptozotocin-induced (STZ-induced) hyperglycaemia in the rat brain and spinal cord. A total of 40 rats were used in this study. Rats were divided into four groups: sham-control, diabetic, diabetic-etomidate treated and vehicle for etomidate treatment group. Diabetes mellitus was induced by a single injection of streptozotocin (60 mg/kg body weight). Three days after streptozotocin injection, etomidate (2 mg/kg) was injected intraperitoneally for etomidate group and lipid emulsion (10%) for vehicle group was injected with corresponding amount intraperitoneally every day for 6 weeks. Six weeks after streptozotocin injection, seven rats from each group were killed and brain, brain stem and cervical spinal cord were removed. The hippocampus, cortex, cerebellum, brain stem and spinal cord were dissected for the biochemical analysis (the level of malondialdehyde [MDA], total nitrite, reduced glutathione [GSH], and xanthine oxidase [XO] activity). STZ-induced diabetes resulted in significantly elevation of MDA, XO and nitrite levels in the hippocampus, cortex, cerebellum, brain stem and spinal cord of the rats (P < 0.05) while etomidate treatment provided significantly lower values (P < 0.05). This study demonstrated that etomidate have neuroprotective effect on the neuronal tissue against the diabetic oxidative damage.

Neuroprotective effect of etomidate on functional recovery in experimental spinal cord injury.

OBJECTIVE: Primary impact to the spinal cord causes rapid oxidative stress after injury. To protect neural tissue, it is important to prevent secondary pathophysiological mechanisms. Etomidate, a strong antiexcitotoxic agent, stimulates the gamma aminobutyric acid (GABA) receptors. The purpose of this study was to investigate neurobehavioral and histological recovery and to evaluate the biochemical responses to treatment of experimental spinal cord injury (SCI) in rats with etomidate or methylprednisolone (MP) or both etomidate and MP. MATERIAL AND METHODS: Seventy-two rats were randomly allocated into six groups: a control group (laminectomy alone), a trauma group (laminectomy+trauma), a methylprednisolone group (30 mg/kg MP), an etomidate group (2 mg/kg), a methylprednisolone and etomidate combined treatment group (30 mg/kg MP and 2 mg/kg etomidate) and a vehicle group. Six rats from each group were killed at the 24th hour after the injury. Malondialdehyde, glutathione, nitric oxide and xanthine oxidase levels were measured. Neurological functions of the remaining rats were recorded weekly. Six weeks after injury, all of those rats were killed for histopathological assessment. RESULTS: Etomidate treatment revealed similar neurobehavioral and histopathological recovery to MP treatment 6 weeks after injury. Combined treatment did not provide additional neuroprotection. CONCLUSION: Etomidate treatment immediately after spinal cord injury has similar neuroprotection to MP. In spite of different neuroprotection mechanisms, combined treatment with MP and etomidate does not provide extra protection.