oxadiazoles and Huntington-Disease

1. Caspases, key enzymes in the apoptosis pathway, have been detected in the brain of HD patients and in animal models of the disease. In the present study, we investigated the neuroprotective properties of a new, reversible, caspase-3-specific inhibitor, M826 (3-([(2S)-2-[5-tert-butyl-3-[[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]amino]-2-oxopyrazin-1(2H)-yl]butanoyl]amino)-5-[hexyl(methyl)amino]-4-oxopentanoic acid), in a rat malonate model of HD. 2. Pharmacokinetic and autoradiography studies after intrastriatal (i.str.) injection of 1.5 nmol of M826 or its tritiated analogue [(3)H]M826 indicated that the compound diffused within the entire striatum. The elimination half-life (T(1/2)) of M826 in the rat striatum was 3 h. 3. I.str. injection of 1.5 nmol of M826 10 min after malonate infusion induced a significant reduction (66%) in the number of neurones expressing active caspase-3 in the ipsilateral striatum. 4. Inhibition of active caspase-3 translated into a significant but moderate reduction (39%) of the lesion volume, and of cell death (24%), 24 h after injury. The efficacy of M826 at inhibiting cell death was comparable to that of the noncompetitive NMDA receptor antagonist MK801. 5. These data provide in vivo proof-of-concept of the neuroprotective effects of reversible caspase-3 inhibitors in a model of malonate-induced striatal injury in the adult rat.

Topics: Animals; Autoradiography; Caspase 3; Caspase Inhibitors; Cell Count; Cell Death; Diffusion; Dizocilpine Maleate; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Excitatory Amino Acid Antagonists; Half-Life; Huntington Disease; Male; Malonates; Neostriatum; Neurons; Neuroprotective Agents; Oxadiazoles; Pyrazines; Rats; Rats, Sprague-Dawley

The density of calcium channel antagonist receptors labeled by (+)-[3H]PN 200-110 was reduced by 75% in striata from patients with Huntington's disease, but unchanged in patients with Parkinson's disease, compared with control subjects. These receptors are therefore likely to be localized to neurons with cell bodies in striatum, rather than nigrostriatal nerve terminals or glia, and their loss may contribute to the pathophysiology of basal ganglia disorders.

Topics: Aged; Calcium Channel Blockers; Corpus Striatum; Humans; Huntington Disease; Isradipine; Middle Aged; Nerve Degeneration; Neural Pathways; Neurons; Oxadiazoles; Parkinson Disease; Substantia Nigra

Exposure of cultures of cortical cells from mouse to either of the endogenous excitatory neurotoxins quinolinate or glutamate resulted in widespread neuronal destruction; but only in the cultures exposed to quinolinate, an N-methyl-D-aspartate agonist, was there a striking preservation of the subpopulation of neurons containing the enzyme nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d). Further investigation revealed that neurons containing NADPH-d were also resistant to the toxicity of N-methyl-D-aspartate itself but were selectively vulnerable to the toxicity of either kainate or quisqualate. Thus, neurons containing NADPH-d may have an unusual distribution of receptors for excitatory amino acids, with a relative lack of N-methyl-D-aspartate receptors and a relative preponderance of kainate or quisqualate receptors. Since selective sparing of neurons containing NADPH-d is a hallmark of Huntington's disease, the results support the hypothesis that the disease may be caused by excess exposure to quinolinate or some other endogenous N-methyl-D-aspartate agonist.

Topics: Animals; Aspartic Acid; Glutamates; Glutamic Acid; Humans; Huntington Disease; Kainic Acid; Mice; N-Methylaspartate; NADH, NADPH Oxidoreductases; NADPH Dehydrogenase; Neurons; Oxadiazoles; Pyridines; Quinolinic Acid; Quinolinic Acids; Quisqualic Acid