Sergei Belyakov

Neuroprotective Effects of Inhibitors of Dipeptidyl Peptidase-IV In Vitro and In Vivo

For the first time, we demonstrated both neuroprotective and neuroregeneratrive effects of common DPP-IV inhibitors in vitro and in vivo. DPP IV inhibitors protect motor neurons from excitotoxic cell death. They are systemically active and protect striatal innervation of dopaminergic neurons, when administered concurrently with MPTP. Furthermore, DPP-IV inhibitors promote recovery of striatal innervation density when given in a therapeutic manner following MPTP treatment. These data suggest that DPP IV inhibitors may provide protective effects on neurons and promote their use as therapies for treatment of neurodegenerative disorders.

DPP IV inhibitor blocks mescaline-induced scratching and amphetamine-induced hyperactivity in mice.

Dipeptidyl peptidase IV (DPP IV) is a ubiquitous membrane-bound enzyme that cleaves the two N-terminal amino acids from peptides with a proline or alanine residue in the second position from the amino end. Potential substrates for DPP IV include several neuropeptides, suggesting a role for DPP IV in neurological processes. We have developed a potent DPP IV inhibitor (IC50 = 30 nM), 1-(2-amino-3-methyl-butyryl)-azetidine-2-carbonitrile (AMAC), which has shown efficacy in two established models of psychosis: mescaline-induced scratching and amphetamine-induced hyperactivity. In the mescaline-induced scratching model, AMAC treatment before mescaline administration reduced the number of scratching paroxysms by 68% (P < 0.01). The compound showed a dose-dependent effect, inhibiting significantly at 6, 20 and 60 mg/kg (37%, 39% and 68%, respectively). In the amphetamine-induced hyperactivity model, 50 and 60 mg/kg AMAC, given before injection of amphetamine, significantly reduced hyper-locomotion by 65% and 76%, respectively. Additionally, AMAC showed no significant activity in binding assays for 20 receptors thought to be involved in the pathology of schizophrenia, including dopamine, serotonin and glutamate. A structurally similar analog, 1-(2-dimethylamino-3-methyl-butyryl)-azetidine-2-carbonitrile (DAMAC), that does not inhibit DPP IV, was inactive in both models. Taken together, these data suggest that the antipsychotic effects of AMAC are the result of DPP IV inhibition.