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.
Bezard
Erwan
E
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
Gerlach
Irene
I
Moratalla
Rosario
R
Gross
Christian E
CE
Jork
Reinhard
R
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