Effect of Clemizole on Alpha-Synuclein-Preformed Fibrils-Induced Parkinson's Disease Pathology: A Pharmacological Investigation.

Parkinson's disease (PD) is a neurodegenerative disorder associated with mitochondrial dysfunctions and oxidative stress. However, to date, therapeutics targeting these pathological events have not managed to translate from bench to bedside for clinical use. One of the major reasons for the lack of translational success has been the use of classical model systems that do not replicate the disease pathology and progression with the same degree of robustness. Therefore, we employed a more physiologically relevant model involving alpha-synuclein-preformed fibrils (PFF) exposure to SH-SY5Y cells and Sprague Dawley rats. We further explored the possible involvement of transient receptor potential canonical 5 (TRPC5) channels in PD-like pathology induced by these alpha-synuclein-preformed fibrils with emphasis on amelioration of oxidative stress and mitochondrial health. We observed that alpha-synuclein PFF exposure produced neurobehavioural deficits that were positively ameliorated after treatment with the TRPC5 inhibitor clemizole. Furthermore, Clemizole also reduced p-alpha-synuclein and diminished oxidative stress levels which resulted in overall improvements in mitochondrial biogenesis and functions. Finally, the results of the pharmacological modulation were further validated using siRNA-mediated knockdown of TRPC5 channels, which also decreased p-alpha-synuclein expression. Together, the results of this study could be superimposed in the future for exploring the beneficial effects of TRPC5 channel modulation for other neurodegenerative disorders and synucleopathies.

Activation of mGlu 2/3 receptors with the orthosteric agonist LY-404,039 alleviates dyskinesia in experimental parkinsonism.

LY-404,039 is an orthosteric agonist at metabotropic glutamate 2 and 3 (mGlu 2/3 ) receptors, with a possible additional agonist effect at dopamine D 2 receptors. LY-404,039 and its pro-drug, LY-2140023, have previously been tested in clinical trials for psychiatric indications and could therefore be repurposed if they were shown to be efficacious in other conditions. We have recently demonstrated that the mGlu 2/3 orthosteric agonist LY-354,740 alleviated L-3,4-dihydroxyphenylalanine (L-DOPA)-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat without hampering the anti-parkinsonian action of L-DOPA. Here, we seek to take advantage of a possible additional D 2 -agonist effect of LY-404,039 and see if an anti-parkinsonian benefit might be achieved in addition to the antidyskinetic effect of mGlu 2/3 activation. To this end, we have administered LY-404,039 (vehicle, 0.1, 1 and 10 mg/kg) to 6-OHDA-lesioned rats, after which the severity of axial, limbs and oro-lingual (ALO) AIMs was assessed. The addition of LY-404,039 10 mg/kg to L-DOPA resulted in a significant reduction of ALO AIMs over 60-100 min (54%, P  < 0.05). In addition, LY-404,039 significantly enhanced the antiparkinsonian effect of L-DOPA, assessed through the cylinder test (76%, P  < 0.01). These results provide further evidence that mGlu 2/3 orthosteric stimulation may alleviate dyskinesia in PD and, in the specific case of LY-404,039, a possible D 2 -agonist effect might also make it attractive to address motor fluctuations. Because LY-404,039 and its pro-drug have been administered to humans, they could possibly be advanced to Phase IIa trials rapidly for the treatment of motor complications in PD.

Delayed levodopa-responsive parkinsonism following acute midbrain injury.

Acute midbrain injury may cause both hyperkinetic movement disorders and parkinsonism. The temporal interval between the insult and the emergence of hyperkinetic disorders can last years. A delayed appearance of parkinsonism, on the other hand, was rarely described. We present three cases of male patients (50-, 58- and 28-year-old) who developed levodopa-responsive parkinsonism 20, 8 and two years, respectively, after acute brain insult involving the midbrain. Insults included subcortical intracerebral hemorrhage dissecting into the midbrain, embolic basilar occlusion and trauma. A fluorodopa scan, performed in two cases, revealed reduced striatal uptake. All individuals improved on low doses of levodopa and developed motor fluctuations shortly after levodopa was introduced. We conclude that delayed, levodopa-responsive parkinsonism following midbrain injury should be recognized in the relevant clinical setup. Possible mechanisms include age-related loss of dopaminergic neurons superimposed on acute injury and secondary neurodegeneration.

Thymoquinone ameliorates symptoms of Parkinson's disease in a 6-OHDA rat model by downregulation of miR-204-3p.

microRNAs (miRNAs) play a significant role in the pathophysiology of Parkinson's disease. In this study, we evaluated the neuroprotective effect of thymoquinone on the expression profiles of miRNA and cognitive functions in the 6-hydroxydopamine (6-OHDA)-induced Parkinson's model. Male adult Wistar albino rats (200-230 g, n  = 36) were randomly assigned to six groups: Sham, thymoquinone (10 mg/kg, p.o.), 6-OHDA, 6-OHDA + thymoquinone (10 mg/kg), 6-OHDA + thymoquinone (20 mg/kg), and 6-OHDA + thymoquinone (50 mg/kg). Behavioral changes were detected using the open field and the elevated plus maze tests. The mature 728 miRNA expressions were evaluated by miRNA microarray (GeneChip miRNA 4.0). Ten miRNAs were selected (rno-miR-212-5p, rno-miR-146b-5p, rno-miR-150-5p, rno-miR-29b-2-5p, rno-miR-126a-3p, rno-miR-187-3p, rno-miR-34a-5p, rno-miR-181d-5p, rno-miR-204-3p, and rno-miR-30c-2-3p) and confirmed by real-time PCR. Striatum samples were stained with hematoxylin-eosin to determine the effect of dopaminergic lesions. One-way ANOVA test and independent sample t -test were used for statistical analyses. rno-miR-204-3p was upregulated at 6-OHDA and downregulated at the 50 mg/kg dose of thymoquinone. In conclusion, thymoquinone at a dose of 50 mg/kg ameliorates symptoms of Parkinson's disease in a 6-OHDA rat model by downregulation of miR-204-3p. Also, the results showed that thymoquinone can improve locomotor activity and willing exploration and decreased anxiety. Therefore, thymoquinone can be used as a therapeutic agent.

Unveiling the therapeutic prospects of EGFR inhibition in rotenone-mediated parkinsonism in rats: Modulation of dopamine D3 receptor.

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. The dopamine D3 receptor (D3R) plays a significant role in the pathogenesis and treatment of PD. Activation of receptor tyrosine kinases (RTKs) inhibits signaling mediated by G protein-coupled receptor (GPCR). Epidermal growth factor receptors (EGFRs) and dopamine D3 receptors in the brain are directly associated with PD, both in terms of its development and potential treatment. Therefore, we investigated the impact of modulating the EGFR, a member of the RTKs family, and the dopamine D3R, a member of the GPCR family. In the present study, 100 mg/kg of lapatinib (LAP) was administered to rotenone-intoxicated rats for three weeks. Our findings indicate that LAP effectively alleviated motor impairment, improved histopathological abnormalities, and restored dopaminergic neurons in the substantia nigra. This restoration was achieved through the upregulation of dopamine D3R and increase of tyrosine hydroxylase (TH) expression, as well as boosting dopamine levels. Furthermore, LAP inhibited the activity of p-EGFR, GRK2, and SCR. Additionally, LAP exhibited antioxidant properties by inhibiting the 4-hydroxynonenal (4-HNE) and PLCγ/PKCßII pathway, while enhancing the antioxidant defense mechanism by increasing GSH-GPX4 pathway. The current study offers insights into the potential repositioning of LAP as a disease-modifying drug for PD. This could be achieved by modulating the dopaminergic system and curbing oxidative stress.

Striatal Serotonin 4 Receptor is Increased in Experimental Parkinsonism and Dyskinesia.

Alterations of serotonin type 4 receptor levels are linked to mood disorders and cognitive deficits in several conditions. However, few studies have investigated 5-HT4R alterations in movement disorders. We wondered whether striatal 5-HT4R expression is altered in experimental parkinsonism. We used a brain bank tissue from a rat and a macaque model of Parkinson's disease (PD). We then investigated its in vivo PET imaging regulation in a cohort of macaques. Dopaminergic depletion increases striatal 5-HT4R in the two models, further augmented after dyskinesia-inducing L-Dopa. Pending confirmation in PD patients, the 5-HT4R might offer a therapeutic target for dampening PD's symptoms.

Antioxidant responses driven by Hesperetin and Hesperidin counteract Parkinson's disease-like phenotypes in Drosophila melanogaster.

The study investigated the protective effects of Hesperetin (HSP) and Hesperidin (HSD) on 1 methyl, 4 phenyl, 1,2,3,6 tetrahydropyridine hydrochloride (MPTP)-induced Parkinsonism in Drosophila melanogaster (D. melanogaster). After a lifespan study to select exposure time and concentrations, flies were co-exposed to MPTP (0.4 mg/g diet), Hesperetin (0.2 and 0.4 mg/g diet), and Hesperidin (0.1 and 0.4 mg/g) for 7 days. In addition to in vivo parameters, we assayed some markers of oxidative stress and antioxidant status (lipid peroxidation, protein carbonylation, thiol content, hydrogen peroxide, and nitrate/nitrite levels, mRNA expression of Keap-1 (Kelch-like ECH associated protein 1), /Nrf2 (Nuclear factor erythroid 2 related factor 2), catalase, and glutathione-S-transferase (GST) activities), and cholinergic (acetyl cholinesterase activity (AChE) and dopaminergic signaling content and the mRNA expression of tyrosine hydroxylase (TH), monoamine oxidase (MAO-like) activity). In addition to increasing the lifespan of flies, we found that both flavonoids counteracted the adverse effects of MPTP on survival, offspring emergence, and climbing ability of flies. Both flavonoids also reduced the oxidative damage on lipids and proteins and reestablished the basal levels of pro-oxidant species and activities of antioxidant enzymes in MPTP-exposed flies. These responses were accompanied by the normalization of the mRNA expression of Keap1/Nrf2 disrupted in flies exposed to MPTP. MPTP exposure also elicited changes in mRNA expression and content of TH as well as in MAO and AChE activity, which were reversed by HST and HSD. By efficiently hindering the oxidative stress in MPTP-exposed flies, our findings support the promising role of Hesperetin and Hesperidin as adjuvant therapy to manage Parkinsonism induced by chemicals such as MPTP.

X-Linked Levodopa-Responsive Parkinsonism-Epilepsy Syndrome: A Novel PGK1 Mutation and Literature Review.

BACKGROUND: Genetic underpinnings in Parkinson's disease (PD) and parkinsonian syndromes are challenging, and recent discoveries regarding their genetic pathways have led to potential gene-specific treatment trials. CASES: We report 3 X-linked levodopa (l-dopa)-responsive parkinsonism-epilepsy syndrome cases due to a hemizygous variant in the phosphoglycerate kinase 1 (PGK1) gene. The likely pathogenic variant NM_000291.4 (PGK1):c.950G > A;p.(Gly317Asp) was identified in a hemizygous state. LITERATURE REVIEW: Only 8 previous cases have linked this phenotype to PGK1, a gene more commonly associated with hemolytic anemia and myopathy. The unusual association of epilepsy, psychiatric symptoms, action tremor, limb dystonia, cognitive symptoms, and l-dopa-responsive parkinsonism must draw attention to PGK1 mutations, especially because this gene is absent from most commercial hereditary parkinsonism panels. CONCLUSIONS: This report aims to shed light on an overlooked gene that causes hereditary parkinsonian syndromes. Further research regarding genetic pathways in PD may provide a better understanding of its pathophysiology and open possibilities for new disease-modifying trials, such as SNCA, LRRK2, PRKN, PINK1, and DJ-1 genes.

Comparing the effect of intravenous versus intracranial grafting of mesenchymal stem cells against parkinsonism in a rat model: Behavioral, biochemical, pathological and immunohistochemical studies.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases worldwide. Currently applied therapeutic protocols are limited to improve the motor functions of patients. Therefore, seeking alternative regimes with better therapeutic impact is crucial. This study aims to validate the therapeutic impact of mesenchymal stem cell injection using two delivery methods, intracranial administration and intravenous administration, on rotenone (ROT)-induced PD model in rats. Our work included behavioral, biochemical, histological, and molecular investigations. Open field test (OFT) and rotarod tests were applied. Important oxidative stress, antioxidant and proinflammatory markers were monitored. Substantia Nigra and Striatum tissues were examined histologically and the molecular expression of DOPA decarboxylase, Tyrosine hydroxylase, and α-synuclein in neurons in these tissues were investigated. Our results showed that MSC grafting improved motor and memory impairments and oxidative stress status that were observed after ROT administration. Additionally, BM-MSCs application restored SOD and CAT activities and the levels of DA, L-Dopa, IL6, IL1ß, and TNFα. Moreover, MSC grafting overwhelmed the pathological changes induced by ROT and normalized the expression of Tyrosine hydroxylase, DOPA decarboxylase, and α-synuclein towards the control values in the Nigral and Striatal tissues of male rats. Conclusively, both administration routes improved motor function, protection of the nigrostriatal system, and improved striatal dopamine release. The observed beneficial effect of applying MSCs suggests potential benefits in clinical applications. No significant differences in the outcomes of the treatment would favor a certain way of MSC application over the other. However, the intravenous delivery method seems to be safer and more feasible compared to the intrastriatal method.

Kinect-based objective assessment of the acute levodopa challenge test in parkinsonism: a feasibility study.

INTRODUCTION: The acute levodopa challenge test (ALCT) is an important and valuable examination but there are still some shortcomings with it. We aimed to objectively assess ALCT based on a depth camera and filter out the best indicators. METHODS: Fifty-nine individuals with parkinsonism completed ALCT and the improvement rate (IR, which indicates the change in value before and after levodopa administration) of the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) was calculated. The kinematic features of the patients' movements in both the OFF and ON states were collected with an Azure Kinect depth camera. RESULTS: The IR of MDS-UPDRS III was significantly correlated with the IRs of many kinematic features for arising from a chair, pronation-supination movements of the hand, finger tapping, toe tapping, leg agility, and gait (rs = - 0.277 ~ - 0.672, P < 0.05). Moderate to high discriminative values were found in the selected features in identifying a clinically significant response to levodopa with sensitivity, specificity, and area under the curve (AUC) in the range of 50-100%, 47.22%-97.22%, and 0.673-0.915, respectively. The resulting classifier combining kinematic features of toe tapping showed an excellent performance with an AUC of 0.966 (95% CI = 0.922-1.000, P < 0.001). The optimal cut-off value was 21.24% with sensitivity and specificity of 94.44% and 87.18%, respectively. CONCLUSION: This study demonstrated the feasibility of measuring the effect of levodopa and objectively assessing ALCT based on kinematic data derived from an Azure Kinect-based system.

Targeting the Nrf2-dependent mechanism of b-Ecdysterone in attenuating the motor dysfunction in the MPTP/Pro-induced Parkinson's disease mice model.

Oxidative stress is a pivotal stimulating factor in neurocyte apoptosis and has been involved in the pathogenesis of Parkinson's disease (PD). In this study, we have demonstrated that the improvement in the motor disorder of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/Pro-induced mice caused by b-Ecdysterone (b-Ecd) treatment is due to its antioxidant properties. Using open field, rotarod, and pole climbing tests, we have found that b-Ecd alleviates motor disorder in MPTP/Pro-induced mice and ultimately reduces the impairment of tyrosine hydroxylase (TH)-positive dopaminergic neurons in the substantia nigra (SN). Notably, these effects of b-Ecd were not observed in Nrf2-KO mice. In addition, b-Ecd significantly reduced the formation of ROS and the level of MDA, blocked the increase of LPO, and partially reversed the GSH/GSSG ratio in MPTP/Pro-induced WT mice; however, these results were also not observed in MPTP/Pro-induced Nrf2-KO mice. Mechanistically, b-Ecd enhanced the expression levels of heme oxygenase 1 (HO-1) and GCLc, but not NQO1 (NAD(P)H quinone dehydrogenase 1) and GCLm expression. Interestingly, b-Ecd failed to increase the protein and mRNA levels of HO-1 and GCLc in Nrf2-KO mice, suggesting that b-Ecd attenuates oxidative stress through an Nrf2-dependent mechanism. Furthermore, b-Ecd promoted the expressions of PI3K/Akt phosphorylation (activity) and GSK-3b phosphorylation (inactivity). Conversely, administration of b-Ecd markedly decreased Fyn phosphorylation levels. Collectively, our findings suggest that b-Ecd focuses on Nrf2 in reducing MPTP/Pro-induced oxidative stress and subsequent motor deficits by inhibiting its nuclear export through PI3K/Akt/GSK-3b/Fyn pathway regulation. These further indicate that b-Ecd may be an absorbing therapeutic agent for PD.

The 5-HT2A/2C inverse agonist nelotanserin alleviates L-DOPA-induced dyskinesia in the MPTP-lesioned marmoset.

Nelotanserin is a serotonin 2A and 2C (5-HT2A/2C) inverse agonist that was previously tested in the clinic for rapid-eye movement sleep behaviour disorder and psychosis in patients with Parkinson's disease (PD) dementia. Its effect on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia has however not been investigated. As 5-HT2A antagonism/inverse agonism is a validated approach to alleviate dyskinesia, we undertook the current study to evaluate the anti-dyskinetic potential of nelotanserin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Parkinsonism was induced in six common marmosets (Callithrix jacchus, three females and three males) that were then chronically treated with L-DOPA to induce dyskinesia. On experimental days, they were administered L-DOPA in combination with vehicle or nelotanserin (0.1, 0.3 and 1 mg/kg) subcutaneously, in a randomised fashion. Dyskinesia and parkinsonism were rated post hoc by a blinded observer. In comparison to vehicle, the addition of nelotanserin 0.3 and 1 mg/kg to L-DOPA diminished peak dose dyskinesia by 47% (P < 0.05) and 69% (P < 0.001). Nelotanserin 0.3 and 1 mg/kg also reduced the severity of global dyskinesia, by 40% (P < 0.01) and 55% (P < 0.001), when compared to vehicle. Nelotanserin 0.1 mg/kg did not alleviate peak dose or global dyskinesia severity. Nelotanserin had no impact on the anti-parkinsonian action of L-DOPA. Our results highlight that nelotanserin may represent an efficacious anti-dyskinetic drug and provide incremental evidence of the potential benefit of 5-HT2A/2C antagonism/inverse agonism for drug-induced dyskinesia in PD.

Supplementation with vitamins D3 and a mitigates Parkinsonism in a haloperidol mice model.

BACKGROUND: Earlier reports suggest that vitamin D3 (Vit D3) supplementation attenuates Parkinsonism in drug-induced motor deficits. Moreover, the function of Vit D3 may be optimized by co-administration with vitamin A (Vit A). In line with the synergistic interplay between vitamins, we hypothesized that the efficacy of Vit D3 to attenuate Parkinsonism in a haloperidol-induced mouse model of motor deficits would be more potent when concomitantly administered with Vit A. METHODS: Thirty-six (36) adult male mice were randomly divided into six groups of six animals each: the control group, the PD model (haloperidol-treated only group) (-D2), and four other groups treated with haloperidol together with either one or two of the following vitamin supplementations: Vit D3, Vit A, Vit D3 +VA, or bromocriptine a known PD drug respectively. Motor functions were assessed using a battery of neurobehavioral tests in experimental animals, after which brain tissues were harvested and processed for biochemical and histomorphological analysis. RESULTS: We recorded a significant decline in motor activity in the PD mice model treated with haloperidol alone compared to other experimental groups that received vitamin supplementations. The significant decrease in motor activity observed in the PD mice model corresponded with marked neurodegenerative features in the cytoarchitecture of the pyramidal cells in the striatum and primary motor cortex (M1). Furthermore, the haloperidol-induced PD mice model treated with Vit D3 +Vit A showed significant improvement in motor activity and attenuation of oxidative stress levels and neurodegenerative features compared to other groups treated with Vit A, Vit D3 and bromocriptine alone. CONCLUSION: Altogether, our findings suggest that concomitant administration of both Vit D3 and Vit A prevents the development of Parkinsonism features in the haloperidol mouse model of motor deficit. Thus, supplementation with Vit D3 +Vit A may be a viable option for slowing the onset and progression of motor deficits.

Botulinum toxin treatment in parkinsonism.

Botulinum toxin (BoNT) was approved by the United States Food and Drug Administration (FDA) in 1989 for facial movement disorders and strabismus, but since that time its indications have been expanding beyond neurologic and ophthalmologic disorders. This article is a narrative review of the therapeutic use of BoNT in tremors, dystonia, sialorrhea, bladder and other autonomic symptoms, levodopa-induced dyskinesia and other problems occuring in the setting of parkinsonism. Though FDA approval is lacking for some of these indications, expert experiences have shown that BoNT is often beneficial in this group of patients.

Icariin attenuates dopaminergic neural loss in haloperidol-induced Parkinsonism in rats via GSK-3ß and tyrosine hydroxylase regulation mechanism.

Parkinson's Disease (PD) is an age-dependent, incessant, dynamic neurodegenerative illness. In animal models, the administration of the dopaminergic D2 antagonist Haloperidol (HP) affects the nigrostriatal pathway, inducing catalepsy, a state of immobility like PD, bradykinesia, and akinesia. The present study investigated the neural effects of Icariin (ICA), a flavonoid derived from Herba Epimedii, against HP-induced PD in rats compared to a standard drug levodopa (L-DOPA). Twenty-four adult male rats were divided into 4 groups: the control group treated with vehicle, the 2nd group treated with HP intraperitoneally, the 3rd group treated with the same dose of HP+L-DOPA orally, and the 4th one, treated with the same dose of HP+ICA orally. All the groups were treated for fourteen consecutive days. Two days before the last dose, locomotor activity was assessed in open field and rotarod tasks. At the end of the experiment, the malondialdehyde, nitric oxide (NO), iron, glycogen synthase kinase-3beta (GSK-3ß), and tyrosine hydroxylase (TH) contents, glutathione S-transferase, catalase, superoxide dismutase, activities were estimated in the midbrain. Also, cortex and midbrain monoamine contents (norepinephrine, dopamine, and serotonin) were determined. Moreover, the midbrain histopathology was detected in all treated groups. The results suggested that the neuroleptic effect of HP was completely improved by ICA. This improvement occurred by decreasing the neurotoxicity via lowering midbrain lipid peroxidation, NO, GSK-3ß contents, increasing antioxidant biomarkers, TH, and recovering the treated groups' cortex and midbrain monoamines contents. In conclusion, this study suggests that ICA is a suitable treatment for Parkinson's induced by HP.

Safety outcomes of antipsychotics classes in drug-naïve patients with first-episode schizophrenia: A nationwide cohort study in South Korea.

INTRODUCTION: Given the similar efficacies across antipsychotic medications for schizophrenia, understanding their safety profiles, particularly concerning receptor-binding differences, is crucial for optimal drug selection, especially for patients with first episode schizophrenia. We aimed to compare the safety outcomes of second-generation antipsychotics. METHODS: We conducted a retrospective cohort study with new user active comparator design using a nationwide claims database in South Korea. Participants were drug-naïve adult patients with first-episode schizophrenia. Three representative drugs with different pharmacologic profiles were compared: risperidone, olanzapine, and aripiprazole. Propensity scores were used to match the study groups, and the Cox proportional hazard model was used to calculate hazard ratios. Sensitivity analyses were performed in various epidemiological settings. Seventeen safety outcomes, including neuropsychiatric, cardiometabolic and gastrointestinal events, were assessed, with upper-respiratory-tract infection as a negative control outcome. RESULTS: A total of 1044, 2078, and 3634 participants were matched for olanzapine vs. risperidone, olanzapine vs. aripiprazole, and risperidone vs. aripiprazole comparisons, respectively. For parkinsonism, there was a significant difference in outcomes between the risperidone and aripiprazole groups (HR 1.80 [95% CI 1.13-2.91]), with consistent sensitivity analysis results. There were no significant differences in other neuropsychiatry outcomes or in the risk of cardiometabolic and gastrointestinal outcomes between any of the comparative group pairs. CONCLUSIONS: The risk of drug-induced parkinsonism was significantly higher with risperidone than with aripiprazole. Although olanzapine is known for its metabolic risk, there were no significant differences in risk between the other pairs.

The Extrapyramidal Symptom Rating Scale and Its Abbreviated Version: A Critical Review of Clinimetric Properties.

BACKGROUND: The Extrapyramidal Symptom Rating Scale - Abbreviated (ESRS-A) is an abbreviated version of the Extrapyramidal Symptom Rating Scale (ESRS) with instructions, definitions, and a semi-structured interview that follows clinimetric concepts of measuring clinical symptoms. Similar to the ESRS, the ESRS-A was developed to assess four types of drug-induced movement disorders (DIMD): parkinsonism, akathisia, dystonia, and tardive dyskinesia (TD). SUMMARY: The present review of the literature provides the most relevant clinimetric properties displayed by the ESRS and ESRS-A in clinical studies. Comprehensive ESRS-A definitions, official scale, and basic instructions are provided. ESRS inter-rater reliability was evaluated in two pivotal studies and in multicenter international studies. Inter-rater reliability was high for assessing both antipsychotic-induced movement disorders and idiopathic Parkinson's disease. Guidelines were also established for inter-rater reliability and the rater certification processes. The ESRS showed good concurrent validity with 96% agreement between Abnormal Involuntary Movement Scale (AIMS) for TD-defined cases and ESRS-defined cases. Similarly, concurrent validity for ESRS-A total and subscores for parkinsonism, akathisia, dystonia, and dyskinesia ranged from good to very good. The ESRS was particularly sensitive for detecting DIMD-related movement differences following treatment with placebo, antipsychotics, and antiparkinsonian and antidyskinetic medications. ESRS measurement of drug-induced extrapyramidal symptoms was shown to discriminate extrapyramidal symptoms from psychiatric symptoms. KEY MESSAGES: The ESRS and ESRS-A are valid clinimetric indices for measuring DIMD. They can be valuably implemented in clinical research, particularly in trials testing antipsychotic medications, and in clinics to detect the presence, severity, and response to treatment of movement disorders.

Neuroprotective effects of isatin and afobazole in rats with rotenone-induced Parkinsonism are accompanied by increased brain levels of Triton X-100 soluble alpha-synuclein.

Effects of the endogenous neuroprotector isatin and the pharmacological drug afobazole (exhibiting neuroprotective properties) on behavioral reactions and quantitative changes in the brain proteomic profile have been investigated in rats with experimental rotenone Parkinsonism. A single dose of isatin (100 mg/kg subcutaneously on the last day of a 7-day course of rotenone administration) improved the motor activity of rats with rotenone-induced Parkinsonism in the open field test (horizontal movements) and the rotating rod test. Afobazole (10 mg/kg intraperitoneally, daily during the 7-day course of rotenone administration) reduced the manifestations of rigidity and postural instability. Proteomic analysis, performed using brain samples obtained the day after the last administration of rotenone and neuroprotectors, revealed similar quantitative changes in the brain of rats with rotenone Parkinsonism. An increase in the relative content of 65 proteins and a decrease in the relative content of 21 proteins were detected. The most pronounced changes - an almost ninety-fold increase in the alpha-synuclein content - were found in the brains of rats treated with isatin. In animals of the experimental groups treated with "Rotenone + Isatin", as well as "Rotenone + Afobazole", the increase in the relative content of this protein in the brain was almost 60 and 50 times higher than the control values. Taking into consideration the known data on the physiological role of alpha-synuclein, an increase in the content of this protein in the brain upon administration of neuroprotectors to animals with rotenone Parkinsonism may represent a compensatory reaction, at least in the early stages of this disease and the beginning of its treatment.

Novel RAB39B variant associated intellectual disability and levodopa-responsive young-onset parkinsonism.

We report a 37-year-old Caucasian male with history of developmental delay, childhood onset Intellectual Disability (ID) and attention deficit hyperactivity disorder (ADHD) who presented at the age of 34 with tremor-dominant parkinsonism. Next Generation Sequencing (NGS) revealed pathogenic hemizygous sequence variant, c.200G > T, in the RAB39B gene. This report expands the number of described individuals with young onset PD associated with RAB39B mutation.

Naringenin, a Functional Food Component, Improves Motor and Non-Motor Symptoms in Animal Model of Parkinsonism Induced by Rotenone.

Parkinson's disease (PD) and other age-related neurodegenerative ailments have a strong link to oxidative stress. Bioflavonoid naringenin has antioxidant properties. The effects of pre- and post-naringenin supplementation on a rotenone-induced PD model were examined in this work. Naringenin (50 mg/kg, p.o.) was administered to rats for two weeks before the administration of rotenone in the pre-treatment phase. In contrast, rotenone (1.5 mg/kg, s.c.) was administered for eight days before naringenin (50 mg/kg, p.o.) was supplemented for two weeks in the post-treatment phase. During behavioral investigation, the motor and non-motor signs of PD were observed. Additionally, estimation of neurochemical and biochemical parameters was also carried out. Compared to controls, rotenone treatment substantially increased oxidative stress, altered neurotransmitters, and caused motor and non-motor impairments. Rotenone-induced motor and non-motor impairments were considerably reduced by naringenin supplementation. The supplementation also increased antioxidant enzyme activities and restored the changes in neurotransmitter levels. The findings of this work strongly imply that daily consumption of flavonoids such as naringenin may have a therapeutic potential to combat PD.