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Acetylcholine muscarinic receptors (mAChRs) contribute to both the facilitation and inhibition of levodopa-induced dyskinesia operated by striatal cholinergic interneurons, although the receptor subtypes involved remain elusive. Cholinergic afferents from the midbrain also innervate the substantia nigra reticulata, although the role of nigral mAChRs in levodopa-induced dyskinesia is unknown. Here, we investigate whether striatal and nigral M1 and/or M4 mAChRs modulate dyskinesia and the underlying striato-nigral GABAergic pathway activation in 6-hydroxydopamine hemilesioned rats. Reverse microdialysis allowed to deliver the mAChR antagonists telenzepine (M1 subtype preferring), PD-102807 and tropicamide (M4 subtype preferring), as well as the selective M4 mAChR positive allosteric modulator VU0152100 in striatum or substantia nigra, while levodopa was administered systemically. Dyskinetic movements were monitored along with nigral GABA (and glutamate) and striatal glutamate dialysate levels, taken as neurochemical correlates of striato-nigral pathway and cortico-basal ganglia-thalamo-cortical loop activation. We observed that intrastriatal telenzepine, PD-102807 and tropicamide alleviated dyskinesia and inhibited nigral GABA and striatal glutamate release. This was partially replicated by intrastriatal VU0152100. The M2 subtype preferring antagonist AFDX-116, used to elevate striatal acetylcholine levels, blocked the behavioral and neurochemical effects of PD-102807. Intranigral VU0152100 prevented levodopa-induced dyskinesia and its neurochemical correlates whereas PD-102807 was ineffective. These results suggest that striatal, likely postsynaptic, M1 mAChRs facilitate dyskinesia and striato-nigral pathway activation in vivo. Conversely, striatal M4 mAChRs can both facilitate and inhibit dyskinesia, possibly depending on their localization. Potentiation of striatal and nigral M4 mAChR transmission leads to powerful multilevel inhibition of striato-nigral pathway and attenuation of dyskinesia., Competing Interests: Declaration of Competing Interest AB is postdoc at the University of Ferrara, CAP is PhD student at the University of Ferrara, MM is employed by the University of Ferrara. The authors declare no competing financial interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Mutations in the nuclear POLG1 gene compromise the integrity of mitochondrial DNA and show great allelic and clinical heterogeneity. Among adult POLG1-associated mitochondrial disease, the main clinical feature is chronic progressive external ophthalmoplegia. Other related clinical manifestations are sensory or cerebellar ataxia, peripheral neuropathy, myopathy or extrapyramidal symptoms. We report the case of a 72-year-old man who presented with a late onset sensory neuronopathy, chronic progressive external ophthalmoplegia, gait ataxia and parkinsonism. Genetic studies showed a compound heterozygosity of known pathogenic mutations in the POLG1 gene (variant T252I/P587 L in cis configuration in allele 1 and variant R807C in allele 2). Late life presentation highlights that mitochondrial disorders should be considered regardless of age of onset of symptoms., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

BACKGROUND Unequivocal brain radiation-induced parkinsonism has so far been reported in only in two pediatric patients. However, with the rising incidence rates for brain tumors in industrialized countries and the consequential increased exposure to cranial radiotherapy, clinicians might become more exposed to this entity. CASE REPORT Three patients were treated for intraparenchymal brain tumor with resection, chemotherapy, and whole brain radiation. One patient developed leukoencephalopathy and parkinsonism within one year of treatment, one developed it seven years after treatment completion, and one developed dementia, parkinsonism and cerebral infracts 40 years after whole brain radiation. Brain MRIs and a DaTscan were obtained. All patients failed a trial of carbidopa/levodopa. We suggest that the brain radiation exposure was responsible for levodopa resistant parkinsonism, cognitive decline, and diffuse leukoencephalopathy. CONCLUSIONS Although rare, radiation therapy-induced parkinsonism might be responsible for levodopa-resistant parkinsonism., Competing Interests: Conflicts of Interest: None declared

Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) often results in debilitating involuntary movements known as L-DOPA-induced dyskinesia (LID), which is the main obstacle in PD. The abnormal involuntary movements (AIMs) are consistently involved with the activation of the Ras-extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signaling pathway. Previous research has also shown that blockade of ERK phosphorylation could reduce the induction of LID. Consequently, inhibitors of MAPK signaling cascade that block the aberrant supersensitive response of direct pathway striatal neurons could provide a novel therapeutic adjunct to L-DOPA in the treatment of PD. Statins, a specific inhibitor of the rate-limiting enzyme in cholesterol biosynthesis, can also inhibit Ras isoprenylation and activity, and the subsequent phosphorylation of ERK1/2 (pERK1/2). Simvastatin, a representative of statins, could reduce L-DOPA-induced AIM incidence and severity in the 6-hydroxydopamine (6-OHDA) rat model of PD by preventing the L-DOPA/benserazide-induced increase in pERK1/2 levels in our study. The simvastatin-L-DOPA/benserazide-treated 6-OHDA animals displayed less severe rotational behavior and a dramatic reduction in AIM severity than the L-DOPA/benserazide-treated ones. This lower AIM severity was related to a decrease in L-DOPA-induced increase in the following: (1) striatal pERK1/2 and (2) FosB levels. These results suggest that simvastatin could represent a treatment option for managing LID in PD.

Chronic treatment with levodopa or antipsychotics results in manifestation of side-effects such as dyskinesia which correlates with changes in expression and function of receptors and signaling proteins. Previous studies have suggested a role for the dopamine D3 receptor in Parkinson's disease (PD) and tardive dyskinesia. Yet the expression and signaling function of D3 receptor in these disorders is not well understood. Here we tested the hypothesis that chronic levodopa treatment alters both expression and function of D3 receptors in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine plus probenecid (MPTP/p) mouse model of PD. drd3-EGFP reporter mice were injected biweekly with saline or MPTP and probenecid for a 5-week period. During the last two weeks of the 5-week period, the mice were administered saline or levodopa twice daily. Locomotor activity was measured during the treatment period. D3 receptor expression was determined by western blot analysis. D3 receptor signaling function was determined at tissue and single cell level by measuring the activation of D3 receptor-mitogen activated protein kinase (MAPK) pathway. The drd3-EGFP mice administered MPTP/p exhibited akinesia/bradykinesia. Expression of D3 receptor protein in the dorsal striatum specifically increased in the MPTP/p-treated mice administered levodopa. In the dorsal striatum of levodopa and MPTP/p-treated drd3-EGFP mice, administration of a D3 receptor-selective dose of agonist, PD128907, failed to activate D3 receptor-MAPK signaling. These results suggest that MPTP-induced lesion and chronic levodopa treatment alters D3 receptor expression and function in the dorsal striatum which could contribute to the development of dyskinesias and other motor side-effects., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Serotonergic 1A (5-HT(1A)) receptor agonists reduce L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia in Parkinson's disease (PD), though the mechanism(s) and site(s) of action remain unclear. We employed [(3)H]-WAY 100,635 autoradiographic receptor binding to measure 5-HT(1A) receptor levels in 4 groups of macaques: normal (vehicle-vehicle); 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned, without exposure to L-DOPA, i.e., untreated parkinsonian (MPTP-vehicle); MPTP-lesioned, receiving a single administration of L-DOPA to alleviate parkinsonism (MPTP-L-DOPA-acute); and MPTP-lesioned, chronically treated with L-DOPA, parkinsonism alleviated but exhibiting dyskinesia (MPTP-L-DOPA-chronic). We demonstrate that 5-HT(1A) receptor binding decreases (by 10%-20%, p < 0.05) in the external layers, but increases (by 80%-100%, p < 0.05) in the middle layers, of the premotor and motor cortex of all MPTP-lesioned macaques. In the striosomes of the caudate nucleus, 5-HT(1A) receptor binding increases in MPTP-vehicle macaques (by 50%, p < 0.05), compared with normal macaques. While 5-HT(1A) receptor binding is low in the matrix of the caudate nucleus in normal macaques, it increases (by 200%, p < 0.05) in MPTP-L-DOPA-chronic macaques. These data suggest that 5-HT(1A) receptors are involved in the pathophysiology of both parkinsonism and complications of L-DOPA therapy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In order to examine the acute effects of L: -DOPA treatment following 6-hydroxydopamine (6-OHDA) injection into rat medial forebrain bundle (MFB). Sprague-Dawley rats (n = 48) received either 6-OHDA, via intracranial unilateral injection, into the MFB (experimental group) or saline 0.9% (control group). Administration of L: -DOPA or saline 0.9% began 1 month after the 6-OHDA injection for 10 consecutive days. Within 3 days, an increase in the density of striatal tyrosine hydroxylase (TH) immunoreactive fibers within the striatum, when compared to the control group was observed. There was no difference in the loss of substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons between. The greater density of TH fibers in the striatum following L: -DOPA may be related to recovery of the DA phenotype and/or sprouting of TH axon terminals. Only animals with severe cell loss in the SNpc experienced abnormal involuntary movements (AIMs) or "dyskinesias" in response to L: -DOPA, which did not correlate with striatal TH fiber density, suggesting that induction of TH-positive fibers does not contribute to the occurrence of dyskinesia. The relationship between cell loss, fiber density and AIM to the abundance of markers of microglial activation were also examined. Iba-1, a microglial marker, immunoreactivity was not affected by L: -DOPA treatment, was not correlated with the severity of AIM indicating that microglial activation does not contribute to dyskinetic phenomena.

A 13-year old girl presented with slowly progressive rest tremor of the hands, bradykinesia, and rigidity. The symptoms improved with dopaminergic medications, but severe drug-induced dyskinesias developed early. She subsequently developed cognitive slowing and difficulty initiating saccadic eye movements. She went on to have deep brain stimulation surgery. Experts discuss the syndromal diagnosis and predict the underlying pathology. The pathological diagnosis is given and clinical learning points are considered., (© 2010 Movement Disorder Society.)

Introduction: Neurocysticercosis (NC) is a chronic parasitary disease that may have different neurological manifestations, such as seizures, dementia or obstructive hydrocephalus. On rare occasions, pictures secondary to hydrocephalia may occur with Parkinsonian syndrome., Case Report: We present the case of a 29-year old woman with serologically confirmed NC and obstructive hydrocephalia secondary to a cyst in the IV ventricle. The patient required repeated ventricle-peritoneal shunt replacement because of valvular malfunction and obstructive hydrocephalia. She developed Parkinsonian's syndrome, which subsided after combined treatment with cysticidal drugs and L-dopa., Discussion: Parkinsonian syndrome is an atypical presentation in NC. In this case, the above-mentioned profile is found within the context of multiple valvular malfunctions who nature is reversible after appropriate treatment. It seems to be related with increases in intraventricular cerebrospinal fluid pressure. We can conclude that Parkinsonian syndromes may be one more expression of NC. This acquires greater importance according to its context, in addition to the limited presence of similar cases in our environment in the literature.

Levodopa remains the mainstay treatment for Parkinson's disease (PD). Chronic treatment is associated with motor complications (MC) that marred the clinical benefit of levodopa. These problems and experimental data in cell cultures indicating a neurotoxic effect of levodopa have led to the idea of delaying the introduction of levodopa treatment for as long as possible. We here review recent data regarding the mechanism of action of levodopa and its application in clinical practice on the light of the marketing of the combination levodopa-carbidopa- entacapone. Accumulated evidence indicates that MC are mainly the consequence of disease severity governing the degree of dopaminergic depletion and the "pulsatile" dopaminergic stimulation provided by levodopa short plasma half-life. There is no in vivo or clinical evidence of a relevant neurotoxic effect of levodopa. In fact, the recent ELLDOPA study may suggest a neuroprotective effect. Entacapone reduces homocysteine plasma levels which could provide a mechanism to reduce cell death in PD. Currently, the combination levodopa-carbidopa-entacapone is particularly indicated for the treatment of "wearing off" fluctuations. Experimental evidence suggests that early treatment with levodopa-carbidopa-entacapone may substantially ameliorate the incidence of MC. Such a clinical study in "de novo" patients is underway. At present, the combination levodopa-carbidopa-entacapone is indicated when levodopa is judged necessary.

We describe a 54-year-old man with dominant adult-onset dopa-responsive dystonia (DRD) with parkinsonism caused by an Arg184His mutation in guanosine 5'-triphosphate cyclohydrolase I (GCH-I). This is the first mutation in the GCH-I gene that has been proven to be responsible for both recessive and dominant phenotypes., (Copyright 2003 Movement Disorder Society)

Three patients with a persistent vegetative state after severe head injury are reported. They recovered from a prolonged disturbance of consciousness after the administration of levodopa. These patients all had parkinsonian features. On magnetic resonance imaging, the distribution of lesions implied a diffuse axonal injury involving the substantia nigra or ventral tegmental area. The existence of patients whose dopaminergic systems may have been selectively damaged by a severe head injury should be recognised because such individuals may respond to levodopa treatment.

Tyrosine hydroxylase deficiency was confirmed biochemically and genetically in four unrelated Dutch patients. The patients have a hypokinetic-rigid parkinsonian syndrome with symptoms in early infancy (3 to 6 months of age). Only sporadic dystonic movements were seen. There was no diurnal fluctuation. All patients showed a rapid favorable response to low-dose L-dopa/carbidopa treatment. Motor performance improved but did not fully normalize. The patients have mild mental retardation.

A bradykinetic form of parkinsonism, unresponsive to levo-dopa therapy developed in four patients two to eight weeks after completion of external beam irradiation (39.2 Gy to 59.4 Gy) of their intracranial neoplasm. In the absence of other causative factors, we relate the movement disorder to radiation-induced changes within the basal ganglia. At post-mortem examination one patient had putamenal gliosis and thickened vessels with loss of nigral neurons.