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 model of NMDA-induced neurodegeneration. Attention was focused on the neuroprotective potential of this combined drug treatment before and after NMDA-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.) 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 given 2 h after the 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.
Stuiver
B T
BT
Department of Animal Physiology, University of Groningen, Haren, The Netherlands.
Douma
B R
BR
Bakker
R
R
Nyakas
C
C
Luiten
P G
PG
D000375:Aging / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000633:toxicity*; D009410:Nerve Degeneration / Q000187:drug effects*; D009412:Nerve Fibers / Q000187:drug effects / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D009553:Nimodipine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D009553:Nimodipine; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate