Tyrosine hydroxylase and dopamine transporter expression in residual dopaminergic neurons: Potential contributors to spontaneous recovery from experimental Parkinsonism

Abstract

1-Methyl-4-phenyl-1,2,3,6-tetrahyrdropyridine (MPTP)-exposed cats develop severe Parkinsonism that spontaneously resolves in 4-6 weeks. The present study examined the extent to which compensatory changes in tyrosine hydroxylase (TH) and dopamine transporter (DAT) gene and protein expression may underlie this behavioral recovery. In normal cats, TH and DAT protein levels were higher in the dorsal vs. ventral striatum. Expression of DAT and TH mRNA was higher in substantia nigra pars compacta (SNc) than in the ventral tegmental area (VTA). In symptomatic parkinsonian animals, DAT and TH protein levels were significantly decreased in all striatal areas studied. TH and DAT mRNA expression in residual SNc neurons were decreased a mean 32% and 38%, respectively. DAT gene expression in residual VTA neurons in symptomatic animals was decreased 30% whereas TH gene expression was unaffected. In spontaneously recovered cats, TH protein levels were significantly higher than the levels in symptomatic cats only in the ventral striatum, whereas no increase in DAT protein levels were observed in any striatal area. Residual neurons in most ventral mesencephalic regions of recovered cats had increased TH mRNA expression but not increased DAT gene expression, compared with symptomatic animals. Thus, increased TH protein and mRNA and suppression of DAT protein and mRNA expression in the striatum and ventral mesencephalon were associated with functional recovery from MPTP-induced parkinsonism.

Neuroprotective Effects of Bak Foong Pill in 1-Methyl-4-phenyl-1,2,3,6-tetrahyrdropyridine (MPTP)-Induced Parkinson's Disease Model Mice

“…Although BFP contains phytoestrogens such as ginseng 37) that may act similarly to estrogen, which has been shown to prevent neuronal degeneration caused by increased oxidative stress 38) and apoptosis 39) ; other component herbs of BFP may act through different mechanisms, the details of which remain to be elucidated. Consistent with our research, TH and DAT gene expression 40,41) and protein patterns 41,42) of dopaminergic neurons have also been described by the other researchers. The intensity of TH-and DAT-immunoreactive dopaminergic cell bodies and terminals was also decreased in the substantia nigra and striatum of mice after MPTP treatment.…”

Motor cortex stimulation: mild transient benefit in a primate model of Parkinson disease

“…These effects may be mediated via direct corticostriatal excitation of striatal DA terminals or via multisynaptic pathways 5 . Such an effect would depend on the presence of residual stores of striatal DA, which have been documented for the mesolimbic striatum of the MPTP-treated primate 7,21,22 . Daily application of MCS may be so frequent as to leave DA terminals in a perpetually depleted state, and consequently provide no therapeutic benefit.…”

Activation of Tyrosine Hydroxylase mRNA Translation by cAMP in Midbrain Dopaminergic Neurons

“…However, when these neurons are only partially destroyed (Ͻ80%), there is considerable recovery of function from these deficits over time. This recovery is due to compensatory mechanisms that occur in the surviving nerve terminals, as well as neuronal sprouting in the nerve terminal regions (Robinson et al, 1990;Zigmond et al, 1990;Bezard et al, 2000;Rothblat et al, 2001;Jakowec et al, 2004). These mechanisms maintain appropriate concentrations Fig.…”

“…In contrast to the vigorous compensatory mechanisms that occur at nerve terminals, only modest or insignificant increases and even decreases in TH mRNA levels are observed in surviving midbrain dopamine cell bodies after lesioning with neurotoxins (Pasinetti et al, 1992;Kastner et al, 1994;Blanchard et al, 1995;Bowyer et al, 1998;Rothblat et al, 2001). Furthermore, TH gene transcription rate does not increase in surviving midbrain cell bodies after lesioning with 6-hydroxydopamine (Sherman and Moody, 1995).…”