Adaptive changes in the nigrostriatal pathway in response to increased 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurodegeneration in the mouse
2000
Although several adaptive mechanisms have been identified that mask the existence of Parkinson's disease and delay the onset and aggravation of motor symptoms, the timescale and implications of this compensatory process remain an enigma. In order to examine: (i) the nature of the
dopaminergicadaptive mechanisms that come into action; (ii) their sequential activation in relation to the severity of degeneration; and (iii) their efficacy with regard to the maintenance of a normal level of basal ganglia activity, we analysed the brains of mice treated daily with 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (
MPTP, 4 mg/kg, i.p.) and killed at 5-day intervals from day 0 (D0) to D20. Our results demonstrate the sequential activation of two compensatory mechanisms: (i) an increase in striatal tyrosine hydroxylase (TH) protein content attested by the persistence of TH
immunolabellingup to D15, contrasting with the decrease observed in both the number of nigral TH-immunoreactive neurons (-70.2%) and striatal dopamine content (-38.4%); (ii) a downregulation of DA uptake in surviving terminals at D20 (73.4% of nigral degeneration). At this point, the failure of adaptive mechanisms to maintain striatal
dopaminergichomeostasis is also illustrated by an increase in the cytochrome oxidase activity of
substantia nigra pars reticulata, a marker of neuronal function. It has been postulated that an increase in dopamine release per pulse could constitute an adaptive mechanism. The data we present from our
MPTPmice model infirm this hypothesis. This study explores the link between the degree of nigral degeneration and the sequential activation of
dopaminergiccompensatory mechanisms in the
nigrostriatal pathwayand, in so doing, proposes a rethink of the paradigm applied to these mechanisms.
Keywords:
-
Correction
-
Source
-
Cite
-
Save
55
References
66
Citations
NaN
KQI