Single intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in C57BL/6 mice models early preclinical phase of Parkinson's disease.
Many studies have shown that deficits in olfactory and cognitive functions precede the classical motor symptoms seen in Parkinson's disease (PD) and that olfactory testing may contribute to the early diagnosis of this disorder. Although the primary cause of PD is still unknown, epidemiological studies have revealed that its incidence is increased in consequence of exposure to certain environmental toxins. In this study, most of the impairments presented by C57BL/6 mice infused with a single intranasal (i.n.) administration of the proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (1 mg/nostril) were similar to those observed during the early phase of PD, when a moderate loss of nigral dopamine neurons results in olfactory and memory deficits with no major motor impairments. Such infusion decreased the levels of the enzyme tyrosine hydroxylase in the olfactory bulb, striatum, and substantia nigra by means of apoptotic mechanisms, reducing dopamine concentration in different brain structures such as olfactory bulb, striatum, and prefrontal cortex, but not in the hippocampus. These findings reinforce the notion that the olfactory system represents a particularly sensitive route for the transport of neurotoxins into the central nervous system that may be related to the etiology of PD. These results also provide new insights in experimental models of PD, indicating that the i.n. administration of MPTP represents a valuable mouse model for the study of the early stages of PD and for testing new therapeutic strategies to restore sensorial and cognitive processes in PD.
Prediger
Rui D S
RD
Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, UFSC, Florianópolis, SC, Brazil. ruidsp@hotmail.com
Aguiar
Aderbal S
AS
Rojas-Mayorquin
Argelia Esperanza
AE
Figueiredo
Claudia P
CP
Matheus
Filipe C
FC
Ginestet
Laure
L
Chevarin
Caroline
C
Bel
Elaine Del
ED
Mongeau
Raymond
R
Hamon
Michel
M
Lanfumey
Laurence
L
Raisman-Vozari
Rita
R
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage; D000281:Administration, Intranasal; D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D015306:Biogenic Monoamines / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D007266:Inhibition, Psychological; D020267:MPTP Poisoning; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009448:Neurochemistry; D009498:Neurotoxins / Q000008:administration & dosage / Q000633:toxicity*; D000857:Olfaction Disorders / Q000209:etiology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000150:complications / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects; D012919:Social Behavior; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D015306:Biogenic Monoamines; D009498:Neurotoxins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase