In Vivo Protection against NMDA-induced Neurodegeneration by MK-801 and Nimodipine: Combined Therapy and Temporal Course of Protection

Abstract

Neuroprotection against excitotoxicity by a combined therapy with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 and the L-type Ca²⁺channel blocker nimodipine was examined using an in vivo rat model of NMDA-induced neurodegeneration. Attention was focused on the neuroprotective potential of this combined drug treatmentbeforeandafterNMDA-exposure. NMDA was unilaterally injected in the magnocellular nucleus basalis (MBN). Neuronal damage was assessed 12 days after the NMDA-injection by measuring the reduction of cholinergic cortical fibres that originate from the MBN neurons. In controls that received no drug treatment, NMDA-exposure damaged MBN neurons such that 66% of the cholinergic terminals were lost in the ipsilateral parietal cortex. Pretreatment with a nimodipine diet (860 ppm) combined with application of MK-801 (5 mg/kg i.p.)beforeNMDA-exposure reduced fibre loss by 89% thereby providing a near complete neuroprotection. Combined therapy of MK-801 (5 mg/kg i.p.) and nimodipine (15 mg/kg i.p.) 8 minafterNMDA-infusion reduced neuronal injury by 82%, while the same combination given 2 hafterthe excitotoxic treatment still yielded a 66% protection against neurotoxic damage invoked by NMDA. In conclusion, the present data show that a dual blockade of NMDA-channels and voltage-dependent calcium channels (VDCC's) up to 2 h after NMDA-exposure is able to provide a significant protection against NMDA-neurotoxicity.