title: A new model to study compensatory mechanisms in MPTP-treated monkeys exhibiting recovery.
abstract: The cardinal symptoms in Parkinson's disease (PD), akinesia, rigidity and tremor, are only observed when the striatal level of dopamine is decreased by 60-80%. During the preclinical phase of PD, compensatory mechanisms are probably involved in delaying the appearance of motor symptoms. In a MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) monkey model of PD, a spontaneous recovery has been reported after initial intoxication suggesting that compensatory mechanisms are activated in this model as well. Assuming that mechanisms are similar in these phenomena, the study of recovery in monkeys following MPTP intoxication may enable identification of compensatory mechanisms involved in the preclinical phase of PD. In order to maximize the temporal similarity between PD and the MPTP model, we assessed a new progressive monkey model in which spontaneous recovery is expressed systematically and to characterize it based on (1) its behavioural features, and (2) the presence of compensatory mechanisms revealed by an immunohistological approach comparing dopaminergic and serotoninergic innervation between monkeys either exhibiting behavioural recovery or stable motor symptoms. This immunohistological study focused on the substantia nigra, striatum and pallidum, and their anatomical and functional subdivisions: sensorimotor, associative and limbic. The behavioural analysis revealed that with progressive MPTP intoxication motor symptoms were initially expressed in all monkeys. Observable recovery from these symptoms occurred in all monkeys (7/7) within 3-5 weeks after the last MPTP injection, and most exhibited a full recovery. In contrast, acute intoxication induced stable motor symptoms. Despite this obvious behavioural difference, immunohistological methods revealed that the loss of dopaminergic cell bodies in substantia nigra was substantial and similar in both MPTP-treated groups. However, quantification of fibres revealed that recovered monkeys displayed more dopaminergic and serotoninergic fibres than those with stable motor symptoms in sensorimotor and associative territories of striatum and more dopaminergic fibres in internal pallidum. This study provides a new model of PD where all monkeys expressed functional recovery from motor symptoms despite a large dopaminergic neuronal loss. The immunohistological results suggest that both dopamine and serotonin could be implicated in the compensatory mechanisms.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 679, Paris F-75013, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Mounayar
authors.forename: Sabrina
authors.initials: S
authors.lastname: Boulet
authors.forename: Dominique
authors.initials: D
authors.lastname: Tandé
authors.forename: Caroline
authors.initials: C
authors.lastname: Jan
authors.forename: Mathias
authors.initials: M
authors.lastname: Pessiglione
authors.forename: Etienne C
authors.initials: EC
authors.lastname: Hirsch
authors.forename: Jean
authors.initials: J
authors.lastname: Féger
authors.forename: Marc
authors.initials: M
authors.lastname: Savasta
authors.forename: Chantal
authors.initials: C
authors.lastname: François
authors.forename: Léon
authors.initials: L
authors.lastname: Tremblay
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D015415:Biomarkers / Q000032:analysis; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000506:poisoning*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000032:analysis / Q000378:metabolism; D005917:Globus Pallidus / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D020267:MPTP Poisoning / Q000523:psychology; D008297:Male; D008636:Mesencephalon / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000473:pathology / Q000523:psychology; D012701:Serotonin / Q000032:analysis / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis / Q000378:metabolism
chemical_list: D015415:Biomarkers; D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D012701:Serotonin; D014446:Tyrosine 3-Monooxygenase