Adaptive changes in the nigrostriatal pathway in response to increased 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced neurodegeneration in the mouse

Abstract

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 dopaminergic adaptive 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 immunolabelling up 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 dopaminergic homeostasis 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 MPTP mice model infirm this hypothesis. This study explores the link between the degree of nigral degeneration and the sequential activation of dopaminergic compensatory mechanisms in the nigrostriatal pathway and, in so doing, proposes a rethink of the paradigm applied to these mechanisms.

Behavioral Recovery in MPTP-Treated Monkeys: Neurochemical Mechanisms Studied by Intrastriatal Microdialysis

“…The latter phenomenon has been reported in spontaneously recovering MPTP cats (Schneider et al, 1994) and rats with partial 6-OHDA lesions (Dentressangle et al, 2001). This diffusion could be facilitated by the volume transmission (Fuxe and Agnati, 1991) promoted under DA depletion (Robinson and Whishaw, 1988) and by a decrease in the number of DA reuptake sites in the striatum (Bezard et al, 2000(Bezard et al, , 2001. We found that associative-limbic DA levels after recovery were similar to those in the normal state.…”

Changes in Gene Expression Linked to Methamphetamine-Induced Dopaminergic Neurotoxicity

“…Interestingly, in addition to a potential role in METH-induced DA neurotoxicity, alterations in COX activity have been reported after lesions induced by several classic neurotoxins, including MPTP, 6-OHDA, and quinolinic acid. For example, COX activity increases in the substantia nigra pars reticulata 20 d after MPTP lesions, with no changes at earlier times (Bezard et al, 2000). Conversely, using similar methods, rats receiving lesions in the striatum with the excitotoxin, quinolinic acid, were noted to have highly significant reductions in COX activity in several basal ganglia structures (including striatum but not substantia nigra pars compacta or pars reticulata) 1 week after injury, whereas rats lesioned with intrastriatal 6-OHDA did not show any changes in COX activity in any of the above regions (Levivier and Donaldson, 2000).…”

Human genetics of plasma dopamine ?-hydroxylase activity: applications to research in psychiatry and neurology

“…These include increased levels (per cell) of tyrosine hydroxylase (TH) mRNA in the substantia nigra and ventral tegmental area (Joyce et al 1997;Tong et al 2000), and TH protein in the striatum (Bezard et al 2000), possibly by increased transcriptional activation of the TH gene. Similar changes in noradrenergic neurons were reported by Burke et al (1999) in a series of AD cases in which substantial (79%) cell loss within the LC was observed together with an 11-fold increase in DβH protein in the remaining neuronal cell bodies.…”