Behavioral motor recovery in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned squirrel monkey (Saimiri sciureus): changes in striatal dopamine and expression of tyrosine hydroxylase and dopamine transporter proteins.

The neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) provides an excellent opportunity to study repair and response to injury in the basal ganglia. Administration to mammals leads to the destruction of nigrostriatal dopaminergic neurons and depletion of striatal dopamine. In the squirrel monkey (Saimiri sciureus), MPTP-lesioning results in parkinsonian motor symptoms including bradykinesia, postural instability, and rigidity. Over time animals display motor behavioral recovery. To better understand this mechanism we employed a lesioning regimen of two or six subcutaneous injections of MPTP (2.0 mg/kg, free-base) to generate mild or moderate parkinsonism. Brain tissue was harvested at 6 weeks or 9 months after the last injection and analyzed for dopamine and its metabolites by high performance liquid chromatography (HPLC), and by immunohistochemical staining and Western immunoblotting for the expression of tyrosine hydroxylase (TH), dopamine transporter (DAT), and dopamine- and cAMP-responsive protein phosphatase of 32 kDa (DARPP-32), an effector molecule enriched in striatal medium spiny neurons. Several months after MPTP-lesioning, when squirrel monkeys displayed full motor behavioral recovery, striatal dopamine levels remained low with a greater return in the ventral striatum. This finding is consistent with other reports using neurotoxicant-lesioning models of the basal ganglia in rodents and other species of nonhuman primates. Elevated dopamine turnover ratio and decreased DAT expression appeared in early behavioral recovery at the 6-week time point in both mild- and moderate-parkinsonian monkeys. Tyrosine hydroxylase and DAT expression was increased in late stage recovery even within dopamine-depleted regions and supports sprouting. Altered DARPP-32 expression suggests a role of medium spiny neurons in recovery.

Petzinger GM ，Fisher B ，Hogg E ，Abernathy A ，Arevalo P ，Nixon K ，Jakowec MW ... -  《JOURNAL OF NEUROSCIENCE RESEARCH》

Tyrosine hydroxylase and dopamine transporter expression following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurodegeneration of the mouse nigrostriatal pathway.

Administration of the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to C57BL/6 mice targets nigrostriatal dopaminergic neurons, leading to cell death and the depletion of striatal dopamine. After MPTP lesioning in young adult mice, surviving nigrostriatal dopaminergic neurons display robust and reproducible return of striatal dopamine weeks to months after injury. Thus, the mouse provides an excellent model with which to investigate the mechanisms underlying neuroplasticity of the nigrostriatal system following neurotoxic injury. The purpose of this study was to analyze proteins and mRNA transcripts of genes involved in dopamine biosynthesis (tyrosine hydroxylase; TH) and uptake (dopamine transporter; DAT) with regard to time course (7-90 days) after MPTP lesioning. Molecular analysis using immunohistochemistry and Western immunoblotting techniques demonstrated an increase in striatal TH by 30-60 days postlesioning that returned to near-control (prelesioned) levels by 60-90 days. In situ hybridization histochemistry indicated that this increase in TH protein might be due in part to increased TH mRNA expression in surviving nigrostriatal dopaminergic neurons. Analysis of TH protein at 7, 30, 60, and 90 days postlesioning with two-dimensional polyacrylamide gel electrophoresis in conjunction with Western immunoblotting revealed altered TH protein isoforms migrating at isoelectric points different from those of the native isoform. In contrast to TH protein, which returned to prelesioned levels by 60 days, DAT protein analysis showed that increased expression of striatal DAT protein did not return to near-prelesion levels until 90 days postlesioning. These results suggest that TH and DAT may differ in their time course of expression in surviving dopaminergic neurons and may play a role in mediating the return of striatal dopamine.

Jakowec MW ，Nixon K ，Hogg E ，McNeill T ，Petzinger GM ... -  《JOURNAL OF NEUROSCIENCE RESEARCH》

Exercise-induced behavioral recovery and neuroplasticity in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse basal ganglia.

Physical activity has been shown to be neuroprotective in lesions affecting the basal ganglia. Using a treadmill exercise paradigm, we investigated the effect of exercise on neurorestoration. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse model provides a means to investigate the effect of exercise on neurorestoration because 30-40% of nigrostriatal dopaminergic neurons survive MPTP lesioning and may provide a template for neurorestoration to occur. MPTP-lesioned C57 BL/6J mice were administered MPTP (four injections of 20 mg/kg free-base, 2 hr apart) or saline and divided into the following groups: (1). saline; (2). saline + exercise; (3). MPTP; and (4) MPTP + exercise. Mice in exercise groups were run on a motorized treadmill for 30 days starting 4 days after MPTP lesioning (a period after which MPTP-induced cell death is complete). Initially, MPTP-lesioned + exercise mice ran at slower speeds for a shorter amount of time compared to saline + exercise mice. Both velocity and endurance improved in the MPTP + exercise group to near normal levels over the 30-day exercise period. The expression of proteins and genes involved in basal ganglia function including the dopamine transporter (DAT), tyrosine hydroxylase (TH), and the dopamine D1 and D2 receptors, as well as alterations on glutamate immunolabeling were determined. Exercise resulted in a significant downregulation of striatal DAT in the MPTP + exercise compared to MPTP nonexercised mice and to a lesser extent in the saline + exercised mice compared to their no-exercise counterparts. There was no significant difference in TH protein levels between MPTP and MPTP + exercise groups at the end of the study. The expression of striatal dopamine D1 and D2 receptor mRNA transcript was suppressed in the saline + exercise group; however, dopamine D2 transcript expression was increased in the MPTP + exercise mice. Immunoelectron microscopy indicated that treadmill exercise reversed the lesioned-induced increase in nerve terminal glutamate immunolabeling seen after MPTP administration. Our data demonstrates that exercise promotes behavioral recovery in the injured brain by modulating genes and proteins important to basal ganglia function.

Fisher BE ，Petzinger GM ，Nixon K ，Hogg E ，Bremmer S ，Meshul CK ，Jakowec MW ... -  《JOURNAL OF NEUROSCIENCE RESEARCH》

Social enrichment attenuates nigrostriatal lesioning and reverses motor impairment in a progressive 1-methyl-2-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease.

Environmental enrichment has been shown to be both neuroprotective and neurorestorative in 1-methyl-2-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse models of Parkinson's disease (PD). However, whether social interaction or novel physical stimulation is responsible for this recovery is controversial. In the current study, we have investigated the effects of only social enrichment (SocE) in progressively MPTP-lesioned mice. After mice were lesioned using a progressively increased dose (4 mg/kg, 8 mg/kg, 16 mg/kg and 32 mg/kg; each dose daily for 5 days), the MPTP-induced behavioral deficits, after the 32 mg/kg dose, were reversed with acute L-DOPA. This acute behavioral recovery suggests that this progressive MPTP-induced neurodegeneration is an appropriate murine model of PD. Mice were housed four per cage for the first 2 weeks of progressive lesioning or vehicle treatment. After the 8 mg/kg MPTP dose (prior to SocE intervention) mice showed a significant decrease in rearing and foot fault behaviors (FF/BB) compared to the vehicle group. Additionally, there was a 38% decrease in mean number of tyrosine hydroxylase immunoreactive (TH-ir) substantia nigra pars compacta (SNpc) neurons/section, and a 50% decrease in the optical density of TH-ir dorsolateral caudate putamen (CPu) terminals compared to the vehicle group. Mice were then housed either two (socially limited environment; SLE) or twelve (SocE) mice per cage during continued MPTP lesioning for the next 2 weeks at 16 mg/kg and 32 mg/kg MPTP. MPTP treatment was then discontinued, while mice remained in the SLE or SocE cages for an additional week. Rearing behavior was further impaired in SLE-MPTP mice following progressive MPTP, accompanied by additional decreases in the mean number of TH-ir SNpc neurons/section and CPu TH-ir terminals. CPu TH and dopamine transporter (DAT) protein expression, as well as dopamine tissue and TH protein levels was significantly decreased compared to either vehicle group. However, the deficit in rearing behavior in SLE-MPTP mice was reversed with acute L-DOPA following the intervention period. SocE-MPTP mice showed rearing and FF/BB behaviors similar to vehicle levels, although FF/BB was not significantly different from pre-intervention levels. The reversal from pre-intervention rearing deficits was correlated with an attenuated decrease in the mean number of SNpc TH-ir neurons/section and CPu TH and DAT protein, and with a blocked decrease in CPu TH-ir terminals compared to pre-intervention levels. Our findings show that SocE mice not only resist further nigrostriatal lesioning and FF/BB deficit, but rearing behavior is recovered to the level of the vehicle group despite continued MPTP treatment. In contrast, SLE mice showed continued loss of nigrostriatal TH-ir and decline of motor behaviors with progressive MPTP. The data suggest that non-pharmacological intervention that started at an early stage of dopamine loss is effective at slowing or blocking further nigrostriatal degeneration.

Goldberg NR ，Fields V ，Pflibsen L ，Salvatore MF ，Meshul CK ... -  《-》

Effects of blocking the dopamine biosynthesis and of neurotoxic dopamine depletion with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on voluntary wheel running in mice.

Leng A ，Mura A ，Hengerer B ，Feldon J ，Ferger B ... -  《BEHAVIOURAL BRAIN RESEARCH》