The anticonvulsant activity and cerebral protection of chronic lithium chloride via NMDA receptor/nitric oxide and phospho-ERK.

The underlying mechanisms for the neuroprotective effects of lithium chloride in neurodegenerative diseases such as seizures remain unknown. In present study the downstream signaling pathway of phospho-ERK/NMDA receptors/nitric oxide has been studied. For this purpose, acute and chronic effect of lithium in seizure animal model and the interaction of NMDA receptor antagonist (MK-801) and neuronal nitric oxide synthase (nNOS) inhibitor (7-NI) with these neuroprotection has been studied. Acute lithium administration showed pro-convulsive properties in pentylenetetrazole (PTZ)-induced seizure model while chronic treatment increased the seizure threshold significantly. The serum level of lithium in treated mice were 0.48 mEq/L corresponding the therapeutic range. Administration of 7-NI (30mg/kg, i.p.) and MK-801 (0.001mg/kg, i.p.) had no effect on seizure threshold, while co-administration of them before the sub-effective dose of lithium (4mg/kg, i.p.) increased the anticonvulsant effect of lithium significantly. Furthermore, acute injection of MK-801 (0.05mg/kg) or 7-NI (60mg/kg) and co-administration of them significantly suppressed the anticonvulsant effect of effective dose of lithium (10mg/kg). This data demonstrated involvement of NMDA receptors/nitric oxide pathway in anticonvulsant effect of lithium. In cerebellar granule neurons (CGNs) culture studies on glutamate excitotoxicity western blot analysis, nitrite assay by Griess reaction, cell viability and microscopic morphology evaluation has been carried out to find the role of NMDA receptor/nitric oxide and phospho-ERK signaling in lithium neuroprotection. Using MTT assay and morphologic examinations, chronic lithium treatment showed protective effects against glutamate toxicity in primary cerebellar culture neurons. The level of nitric oxide was significantly reduced in co-administration of lithium and glutamate while glutamate significantly increased levels of nitric oxide. The involvement of NMDA receptors/nitric oxide and phospho-ERK pathway in the effects of lithium on cerebellar neurons has been shown. Inhibition of ERK signaling may be reconsidered as a pharmacological approach for seizure control.