IN-VIVO PROTECTION AGAINST NMDA-INDUCED NEURODEGENERATION BY MK-801 AND NIMODIPINE - COMBINED THERAPY AND TEMPORAL COURSE OF PROTECTION

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 mode l of NMDA-induced neurodegeneration. Attention was focused on the neur oprotective potential of this combined drug treatment before and after NMDA-exposure. NMDA was unilaterally injected in the magnocellular nu cleus basalis (MEN). Neuronal damage was assessed 12 days after the NM DA-injection by measuring the reduction of cholinergic cortical fibres that originate from the MBN neurons. In controls that received no dru g treatment, NMDA-exposure damaged MBN neurons such that 66% of the ch olinergic terminals were lost in the ipsilateral parietal cortex. Pret reatment with a nimodipine diet (860 ppm) combined with application of MK-801 (5 mg/kg i.p.) before NMDA-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 min after NMDA -infusion reduced neuronal injury by 82%, while the same combination g iven 2 h after the excitotoxic treatment still yielded a 66% protectio n against neurotoxic damage invoked by NMDA. In conclusion, the presen t data show that a dual blockade of NMDA-channels and voltage-dependen t calcium channels (VDCC's) up to 2 h after NMDA-exposure is able to p rovide a significant protection against NMDA-neurotoxicity. (C) 1996 A cademic Press Limited.