Chronic systemic complex I inhibition induces a hypokinetic multisystem degeneration in rats.
In Parkinson's disease, nigral dopaminergic neurones degenerate, whereas post-synaptic striatal target neurones are spared. In some atypical parkinsonian syndromes, both nigral and striatal neurones degenerate. Reduced activity of complex I of the mitochondrial respiratory chain has been implicated in both conditions, but it remains unclear if this affects the whole organism or only the degenerating brain structures. We therefore investigated the differential vulnerability of various brain structures to generalized complex I inhibition. Male Lewis rats infused with rotenone, a lipophilic complex I inhibitor [2.5 mg/kg/day intraveneously (i.v.) for 28 days], were compared with vehicle-infused controls. They showed reduced locomotor activity and loss of striatal dopaminergic fibres (54%), nigral dopaminergic neurones (28.5%), striatal serotoninergic fibres (34%), striatal DARPP-32-positive projection neurones (26.5%), striatal cholinergic interneurones (22.1%), cholinergic neurones in the pedunculopontine tegmental nucleus (23.7%) and noradrenergic neurones in the locus ceruleus (26.4%). Silver impregnation revealed pronounced degeneration in basal ganglia and brain stem nuclei, whereas the hippocampus, cerebellum and cerebral cortex were less affected. These data suggest that a generalized mitochondrial failure may be implicated in atypical parkinsonian syndromes but do not support the hypothesis that a generalized complex I inhibition results in the rather selective nigral lesion observed in Parkinson's disease.
Höglinger
Günter U
GU
INSERM U 289, Experimental Neurology and Therapeutics, Hôpital de la Salpêtrière, Paris, France. gunter@ccr.jussieu.fr
Féger
Jean
J
Prigent
Annick
A
Michel
Patrick P
PP
Parain
Karine
K
Champy
Pierre
P
Ruberg
Merle
M
Oertel
Wolfgang H
WH
Hirsch
Etienne C
EC
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002452:Cell Count; D002795:Choline O-Acetyltransferase / Q000096:biosynthesis; D002908:Chronic Disease; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004334:Drug Administration Schedule; D042967:Electron Transport Complex I; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D002479:Inclusion Bodies / Q000473:pathology; D007262:Infusions, Intravenous; D008125:Locus Coeruleus / Q000187:drug effects / Q000473:pathology; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000473:pathology; D009043:Motor Activity / Q000187:drug effects; D009069:Movement Disorders / Q000150:complications / Q000209:etiology / Q000473:pathology*; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D009419:Nerve Tissue Proteins; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000150:complications / Q000473:pathology*; D009457:Neuroglia / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010575:Pesticides / Q000633:toxicity; D010750:Phosphoproteins / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D012402:Rotenone / Q000008:administration & dosage / Q000633:toxicity*; D012701:Serotonin / Q000096:biosynthesis; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology; D013995:Time; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis
D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D010575:Pesticides; D010750:Phosphoproteins; D012402:Rotenone; D012701:Serotonin; D014446:Tyrosine 3-Monooxygenase; D009247:NADH, NADPH Oxidoreductases; D002795:Choline O-Acetyltransferase; D042967:Electron Transport Complex I