Neuropeptide levels in the basal ganglia of aged common marmosets following prolonged treatment with MPTP

Summary Aged common marmosets were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 0.5–2.0 mg/kg/week i.p.) for 16 or 24 weeks, observed for a total of 30 weeks and then killed for measurement of biochemical pramaters in basal ganglia. The MPTP treatment induced a marked depletion in dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid levels in the caudate nucleus and putamen. In contrast, the concentrations of five neuropeptides: [Met⁵]-enkephalin, [Leu⁵]-enkephalin, cholecystokinin, substance P and neurotensin as measured by a combined HPLC/RIA method, remained unaltered in all basal ganglia regions examined. Enkephalin precursor levels, as reflected by cryptic [Met⁵]-enkephalin content, were increased in the putamen, but not in the caudate nucleus, as a consequence of MPTP administration. Cryptic [Leu⁵]-enkephalin content remained unchanged in the striatum of MPTP treated marmosets. Overall, these results suggest an increase in striatal [Met⁵]-enkephalin release following chronic MPTP treatment of aged marmosets. However, the chronic treatment of aged marmosets with MPTP does not reproduce the neuropeptide alterations characteristic of Parkinson's disease.     

Pathophysiology of idiopathic dystonia: findings from genetic animal models

Dystonia is a common movement disorder which is thought to represent a disease of the basal ganglia. However, the pathogenesis of the idiopathic dystonias, i.e. the neuroanatomic and neurochemical basis, is still a mystery. Research in dystonia is complicated by the existence of various phenotypic and genotypic subtypes of idiopathic dystonia, probably related to heterogeneous dysfunctions.In neurological diseases in which no obvious neuronal degeneration can be found, such as in idiopathic dystonia, the identification of a primary defect is difficult, because of the large number of chemically distinct, but functionally interrelated, neurotransmitter systems in the brain.The variable response to pharmacological agents in patients with idiopathic dystonia supports the notion that the underlying biochemical dysfunctions vary in the subtypes of idiopathic dystonia. Hence, in basic research it is important to clearly define the involved type of dystonia.Animal models of dystonias were described as limited. However, over the last years, there has been considerable progress in the evaluation of animal models for different types of dystonia.Apart from animal models of symptomatic dystonia, genetic animal models with inherited dystonia which occurs in the absence of pathomorphological alterations in brain and spinal cord are described.This review will focus mainly on genetic animal models of different idiopathic dystonias and pathophysiological findings. In particular, in the case of the mutant dystonic (dt) rat, a model of generalized dystonia, and in the case of the genetically dystonic hamster (dt^sz), a model of paroxysmal dystonic choreoathetosis has been used, as these show great promise in contributing to the identification of underlying mechanisms in idiopathic dystonias, although even a proper animal model will probably never be equivalent to a human disease.Several pathophysiological findings from animal models are in line with clinical observations in dystonic patients, indicating abnormalities not only in the basal ganglia and thalamic nuclei, but also in the cerebellum and brainstem. Through clinical studies and neurochemical data several similarities were found in the genetic animal models, although the current data indicates different defects in dystonic animals which is consistent with the notion that dystonia is a heterogenous disorder.Different supraspinal dysfunctions appear to lead to manifestation of dystonic movements and postures. In addition to increasing our understanding of the pathophysiology of idiopathic dystonia, animal models may help to improve therapeutic strategies for this movement disorder.     

GM1 ganglioside partially rescues cultured dopaminergic neurons from MPP-induced damage: dependence on initial damage and time of treatment

GM1 ganglioside is believed to be important in promoting the recovery of neurons from injury. The present study assesses the ability of GM1 to repair or prevent the damage of dopamine neurons caused by the neurotoxin 1-methyl-4-phenylpyridinium (MPP⁺). Treatment of mesencephalic cell cultures with 2.5 μM MPP⁺ resulted in the loss of 30% of tyrosine hydoxylase (TH) immunoreactive neurons. In contrast, cultures administered 100 μM GM1 ganglioside for 3 days after toxin treatment contained nearly control numbers of TH⁺ neurons (97%). This reparative effect of GM1 was reflected in parallel increases in TH enzyme activity, dopamine and dopac levels. Cultures sustaining greater insult from higher doses of MPP⁺ (5.0–10.0 μM) did not benefit from ganglioside treatment, suggesting that rescue by GM1 depended on the degree of initial damage to cells. Moreover, the timing of ganglioside treatment was critical; pretreatment with GM1 alone did not prevent or attenuate the damage caused by subsequent incubation in 2.5 μM MPP⁺.     

Levodopa-induced hyperactivity in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

The present study examines the motor responses of 10- to 12-month-old, male C57 mice that were either given intraperitoneal (IP) injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 30 mg/kg per day) or vehicle for 10 consecutive days, followed by IP injections of levodopa (200 mg/kg) plus carbidopa (25 mg/kg). Five days of MPTP exposure resulted in the Straub tail phenomenon and pronounced hypokinesia. However, during the next 5 days, motor activity returned to baseline, even with continued MPTP treatment. After 10 to 14 days of rest, all mice were then treated with levodopa/carbidopa twice daily for multiple, consecutive days. However, only the previously MPTP-treated animals became hyperkinetic, as compared to levodopa-treated control animals that were not previously exposed to MPTP. Abnormal activity included scratching, running, gnawing, and jumping movements. Hyperactivity lasted for approximately 2 hours after each levodopa injection and then returned to baseline, but the amount of hyperkinesia increased with additional days of levodopa treatment, even though the daily levodopa dose was not changed. These results demonstrate that levodopa can cause reproducible hyperactivity in mice that were previously exposed to MPTP.     

Protective actions of human recombinant basic fibroblast growth factor on MPTP-lesioned nigrostriatal dopamine neurons after intraventricular infusion

Basic fibroblast growth factor (bFGF, FGF-2) is a trophic factor for neurons and astrocytes and has recently been demonstrated in the vast majority of dopamine (DA) neurons of the ventral midbrain of the rat. Potential neuroprotective actions of FGF-2 in the l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) model have also been reported. The actions of the FGF-2 have now been further analyzed in a combined morphological and behavioural analysis in the MPTP model of the adult black mouse, using a continuous human recombinant FGF-2 (hrFGF-2) intraventricular (i.v.t.) administration in a heparin-containing (10 IU heparin/ml) mock cerebrospinal fluid (CSF) solution. Tyrosine hydroxylase (TH) immunocytochemistry in combination with computer assisted microdensitometry demonstrated a counteraction of the MPTP-induced disappearance of neostriatal TH-immunoreactive (ir) nerve terminals following the FGF-2 treatment. Unbiased estimates of the total number of nigral TH ir neurons, using stereological methods involving the optical disector (Olympus), showed that the MPTP-induced reduction in the number of nigral TH ir nerve cell bodies counterstained with cresyl violet (CV; by 56%) was partially counteracted by the FGF-2 treatment (by 26%). The behavioral analysis demonstrated an almost full recovery of the MPTP-induced reduction of the locomotor activity after FGF-2 treatment. This action was maintained also 1 week after cessation of treatment. The hrFGF-2 produced an astroglial reaction as determined in the lateral neostriatum and in the substantia nigra (SN) far from the site of the infusion, indicating that the growth factor may have reached these regions by diffusion to activate the astroglia. Immunocytochemistry revealed FGF-2 immunoreactivity (IR) in the nuclei of the astroglia cell population in the dorsomedial striatum and the microdensitometric and morphometric evaluation demonstrated an increase in the number, but not in the intensity, of these profiles on the cannulated side, suggesting the possibility that hrFGF-2 stimulates FGF-2 synthesis in astroglial cells with low endogenous FGF-2 IR. These results indicate that hrFGF-2, directly and/or indirectly via astroglia, upon i.v.t. infusion exerts trophic effects on the nigrostriatal DA system and may increase survival of nigrostriatal DA nerve cells exposed to the MPTP neurotoxin.     

A chronic mouse model of Parkinson's disease has a reduced gait pattern certainty

The purpose of this investigation was to determine if a chronic Parkinson's disease mouse model will display less certainty in its gait pattern due to basal ganglia dysfunction. A chronic Parkinson's disease mouse model was induced by injecting male C57/BL mice with 10 doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (25 mg/kg) (MPTP) and probenecid (250 mg/kg) (P) over 5 weeks. This chronic model produces a severe and persistent loss of nigrostriatal neurons resulting in dopamine depletion and locomotor impairment. The control mice were treated with probenecid alone. Fifteen weeks after the last MPTP/P treatment, the mice were videotaped in the sagittal plane with a digital camera (60 Hz) as they ran on a motorized treadmill at a speed of 10 m/min. The indices of gait and gait variability were calculated. Stride length was significantly (p = 0.016) more variable in the chronic MPTP/P mice. Additionally, the chronic MPTP/P mice had a statistically less certain gait pattern when compared to the control mice (p = 0.02). These results suggest that variability in the gait pattern can be used to evaluate changes in neural function. Additionally, our results imply that disorder of the basal ganglia results in less certainty in modulating the descending motor command that controls the gait pattern.     

Muscle relaxant action of excitatory amino acid antagonists

Antagonists of neuronal excitation induced by dicarboxylic amino acids were tested in genetically spastic rats of the Han-Wistar strain. These animals exhibit an increased muscle tone which can be measured as a spontaneous tonic activity in the electromyogram of the gastrocnemius-soleus muscle. Compounds that block excitation due to N-methyl-D-aspartic acid reduced the spontaneous activity measured in the electromyogram in a dose-related manner. The most potent compounds, 2-amino-7-phosphonoheptanoic and kynurenic acids were effective muscle relaxants when given either intraperitoneally or intracerebroventricularly. 2-Amino-5-phosphonopentanoic acid possessed much weaker muscle relaxant activity, while L-glutamic acid diethylester was inactive by either route. The results suggest that blockade of N-methyl-D-aspartic acid receptors results in a myorelaxant effect. Specific antagonists of excitation at N-methyl-D-aspartic acid receptors may provide a new class of muscle relaxants.     

Differential effects of acute and chronic nicotine treatment on MPTP-(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced degeneration of nigrostriatal dopamine neurons in the black mouse

Summary Evidence exists for a negative correlation between Parkinson's disease and smoking. The present and previous studies indicate that nicotine treatment can markedly alter the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in the black mouse based on biochemical determinations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels in neostriatum and substantia nigra 2 weeks after MPTP injection. Acute intermittent treatment with (–)nicotine starting 10 min before the MPTP injection partly protected against MPTP-induced neurotoxicity in the neostriatum and substantia nigra. Also, a partial protection was observed in the substantia nigra when (–)nicotine was given together with MPTP in an acute intermittent treatment schedule. Conversely, chronic infusion of (–)nicotine via minipumps produced a dose-related enhancement of MPTP-induced DA neurotoxicity in the neostriatum. It is suggested that the protective activity of nicotine in the MPTP model is related to a blockade of MPP + uptake into the DA cells via increased DA release. Conversely, the nicotine enhancement of MPTP-induced DA toxicity is suggested to be caused by a failure of the nicotinic cholinoceptors to desensitize to the chronic (–)nicotine exposure, leading to increased chronic influx of Na⁺ and Ca²⁺ ions via the ion channels of the nicotinic cholinoceptors located on the DA neurons with associated increased Ca ion toxicity and increased energy demands.Abbreviations DA dopamine - DOPAC 3,4-dihydroxyphenylacetic acid - HPLC high performance liquid chromatography - HVA homovanillic acid - MPP⁺a 1-methyl-4-phenyl-pyridinium ion - MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine     

The interaction of 1-alkyl-4, 4-diphenylpiperidines with the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine receptor binding site

Summary 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) is a selective neurotoxin which produces degeneration of the nigrostriatal bundles in the central nervous system of man and animals. In these areas of the brain are concentrated the receptor binding sites for [³H]MPTP. 1-Alkyl-4, 4-diphenylpiperidines displace [³H]MPTP from these binding sites with K₁ values in the micromolar range. The t-butyl analogue in this class of substances, budipine, is a novel therapeutic agent for Parkinsonism whose mechanism has not yet been fully clarified. The affinity of budipine for the MPTP receptor binding site was determined as a K₁ value of 2.2M. Other 4, 4-diphenylpiperidine derivatives such as 1-methyl-4, 4-diphenylpiperidine and 1-i-propyl-4, 4-diphenylpiperidine have substantially lower affinities. Monoamine oxidase inhibitors such as deprenyl, pargyline and harmaline have affinities to the MPTP receptors which parallel their affinity for the B type of monoamine oxidase (MAO B). This supports the theory that the MPTP receptor binding sites is identical with membrane bound MAO B.