5-HT1A receptor agonist-mediated protection from MPTP toxicity in mouse and macaque models of Parkinson's disease.
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.
CNRS UMR 5543, Laboratoire de Physiologie et Physiopathologie de la Signalisation Cellulaire, Université de Bordeaux 2, 146 rue Leo Saignat, 33076 Bordeaux Cedex, France. erwan.bezard@umr5543.u-bordeaux2.fr
Erwan
E
Bezard
Irene
I
Gerlach
Rosario
R
Moratalla
Christian E
CE
Gross
Reinhard
R
Jork
D000818:Animals; D001578:Benzopyrans / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D017403:In Situ Hybridization; D008251:Macaca; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000188:drug therapy / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use; D020734:Parkinsonian Disorders / Q000517:prevention & control*; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects* / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000627:therapeutic use*; D013844:Thiazoles / Q000627:therapeutic use*; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects / Q000378:metabolism
C513036:BAY 639044; D001578:Benzopyrans; D018696:Neuroprotective Agents; D017366:Serotonin Receptor Agonists; D013844:Thiazoles; D044282:Receptor, Serotonin, 5-HT1A; C111221:repinotan hydrochloride; D014446:Tyrosine 3-Monooxygenase