5-HT1A receptor agonist-mediated protection from MPTP toxicity in mouse and macaque models of Parkinson's disease

Neurobiol Dis. 2006 Jul;23(1):77-86. doi: 10.1016/j.nbd.2006.02.003. Epub 2006 Mar 20.

Abstract

Excitotoxicity-mediated cell death is involved in Parkinson's disease (PD). 5-HT1A receptor agonists can protect from such mechanisms. The current study demonstrates that the 5-HT1A agonists BAY 639044 and repinotan have neuroprotective effects in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. In addition, we also show that both compounds delay the appearance of parkinsonian motor abnormalities in a MPTP monkey model that recapitulates the progressive nature of PD. Thus, BAY 639044 or repinotan treatment was initiated when there was 30% neuronal death in the substantia nigra pars compacta, and nerve terminal loss in the striatum was 40%, i.e., compatible with the clinical situation where early symptomatic patients would receive such a treatment. The delay in appearance of parkinsonian motor abnormalities is a consequence of partial neuroprotection of nigrostriatal dopamine neurons, both at neuronal and terminal levels as shown for BAY 639044. These results suggest that 5-HT1A agonists, such as BAY 639044, may protect from neurodegeneration and delay the worsening of motor symptoms in Parkinson patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzopyrans / therapeutic use
  • Brain / drug effects*
  • Brain / pathology
  • In Situ Hybridization
  • Macaca
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nerve Degeneration / drug therapy
  • Nerve Degeneration / pathology
  • Neurons / drug effects
  • Neurons / pathology
  • Neuroprotective Agents / therapeutic use
  • Parkinsonian Disorders / prevention & control*
  • Receptor, Serotonin, 5-HT1A / drug effects*
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Serotonin Receptor Agonists / therapeutic use*
  • Thiazoles / therapeutic use*
  • Tyrosine 3-Monooxygenase / drug effects
  • Tyrosine 3-Monooxygenase / metabolism

Substances

  • BAY 639044
  • Benzopyrans
  • Neuroprotective Agents
  • Serotonin Receptor Agonists
  • Thiazoles
  • Receptor, Serotonin, 5-HT1A
  • repinotan hydrochloride
  • Tyrosine 3-Monooxygenase