Search Results (13)

Geraniin (GRN), an ellagitannin from Phyllanthus urinaria, shows antioxidant, anti-inflammatory, and neuroprotective effects. This study evaluated GRN’s potential against haloperidol (HPD)-induced orofacial dyskinesia (OD). Rats treated with HPD (1 mg/kg i.p.) for 21 days exhibited dopamine D2 receptor blockade, neurotoxicity, and OD, characterized by vacuous chewing movements (VCM) and tongue protrusion (TP). Then, 60 min post-HPD, GRN was administered i.p. daily for 21 days. OD behaviors were assessed, and on Day 21, striatal tissues were analyzed for oxidative stress, mitochondrial function, inflammation, and apoptosis. GRN alone did not cause OD but significantly reduced HPD-induced VCM and TP. It also reduced oxidative stress, improved antioxidant defense, preserved mitochondrial function, and decreased neuroinflammation and apoptosis. These effects were blocked by ML385, a nuclear factor erythroid-2-related factor 2 (Nrf2) pathway inhibitor. GRN protects against HPD-induced OD, likely via Nrf2 activation. It may be a promising candidate for TD therapy, pending further clinical investigation. Full article

Vitexin (VTX), a C-glycosylated flavone found in various medicinal herbs, is known for its antioxidant, anti-inflammatory, and neuroprotective properties. This study investigated the protective effects of VTX against orofacial dyskinesia (OD) in rats, induced by haloperidol (HPD), along with the neuroprotective mechanisms underlying these effects. OD was induced by administering HPD (1 mg/kg i.p.) to rats for 21 days, which led to an increase in the frequency of vacuous chewing movements (VCMs) and tongue protrusion (TP). VTX (10 and 30 mg/kg) was given intraperitoneally 60 min after each HPD injection during the same period. On the 21st day, following assessments of OD, the rats were sacrificed, and nitrosative and oxidative stress, antioxidant capacity, mitochondrial function, neuroinflammation, and apoptosis markers in the striatum were measured. HPD effectively induced OD, while VTX significantly reduced HPD-induced OD, decreased oxidative stress, enhanced antioxidant capacity, prevented mitochondrial dysfunction, and reduced neuroinflammatory and apoptotic markers in the striatum, and the protective effects of VTX on both behavioral and biochemical aspects of HPD-induced OD were significantly reduced when trigonelline (TGN), an inhibitor of the nuclear factor erythroid-2-related factor 2 (Nrf2)-mediated pathway, was administered. These findings suggest that VTX provides neuroprotection against HPD-induced OD, potentially through the Nrf2 pathway, indicating its potential as a therapeutic candidate for the prevention or treatment of tardive dyskinesia (TD) in clinical settings. However, further detailed research is required to confirm these preclinical findings and fully elucidate VTX’s therapeutic potential in human studies. Full article

The Vps13a gene encodes a lipid transfer protein called VPS13A, or chorein, associated with mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), mitochondria–endosomes, and lipid droplets. This protein plays a crucial role in inter-organelle communication and lipid transport. Mutations in the VPS13A gene are implicated in the pathogenesis of chorea-acanthocytosis (ChAc), a rare autosomal recessive neurodegenerative disorder characterized by chorea, orofacial dyskinesias, hyperkinetic movements, seizures, cognitive impairment, and acanthocytosis. Previous mouse models of ChAc have shown variable disease phenotypes depending on the genetic background. In this study, we report the generation of a Vps13a flox allele in a pure C57BL/6N mouse background and the subsequent creation of Vps13a knockout (KO) mice via Cre-recombination. Our Vps13a KO mice exhibited increased reticulocytes but not acanthocytes in peripheral blood smears. Additionally, there were no significant differences in the GFAP- and Iba1-positive cells in the striatum, the basal ganglia of the central nervous system. Interestingly, we observed abnormal spermatogenesis leading to male infertility. These findings indicate that Vps13a KO mice are valuable models for studying male infertility and some hematological aspects of ChAc. Full article

Tardive dyskinesia (TD) is a hyperkinetic movement disorder that displays unusual involuntary movement along with orofacial dysfunction. It is predominantly associated with the long-term use of antipsychotic medications, particularly typical or first-generation antipsychotic drugs such as haloperidol. Oxidative stress, mitochondrial dysfunction, neuroinflammation, and apoptosis are major pathophysiological mechanisms of TD. The BCG vaccine has been reported to suppress inflammation, oxidative stress, and apoptosis and exert neuroprotection via several mechanisms. Our study aimed to confirm the neuroprotective effect of the BCG vaccine against haloperidol-induced TD-like symptoms in rats. The rats were given haloperidol (1 mg/kg, i.p.) for 21 days after 1 h single administration of the BCG vaccine (2 × 10⁷ cfu). Various behavioral parameters for orofacial dyskinesia and locomotor activity were assessed on the 14th and 21st days after haloperidol injection. On the 22nd day, all rats were euthanized, and the striatum was isolated to estimate the biochemical, apoptotic, inflammatory, and neurotransmitter levels. The administration of the BCG vaccine reversed orofacial dyskinesia and improved motor function in regard to haloperidol-induced TD-like symptoms in rats. The BCG vaccine also enhanced the levels of antioxidant enzymes (SOD, GSH) and reduced prooxidants (MDA, nitrite) and pro-apoptotic markers (Cas-3, Cas-6, Cas-9) in rat brains. Besides this, BCG treatment also restored the neurotransmitter (DA, NE, 5-HT) levels and decreased the levels of HVA in the striatum. The study findings suggest that the BCG vaccine has antioxidant, antiapoptotic, and neuromodulatory properties that could be relevant in the management of TD. Full article

Parkinson’s Disease (PD), treated with the dopamine precursor l-3,4-dihydroxyphenylalanine (L-DOPA), displays motor and non-motor orofacial manifestations. We investigated the pathophysiologic mechanisms of the lateral pterygoid muscles (LPMs) and the trigeminal system related to PD-induced orofacial manifestations. A PD rat model was produced by unilateral injection of 6-hydroxydopamine into the medial forebrain bundle. Abnormal involuntary movements (dyskinesia) and nociceptive responses were determined. We analyzed the immunodetection of Fos-B and microglia/astrocytes in trigeminal and facial nuclei and morphological markers in the LPMs. Hyperalgesia response was increased in hemiparkinsonian and dyskinetic rats. Hemiparkinsonism increased slow skeletal myosin fibers in the LPMs, while in the dyskinetic ones, these fibers decreased in the contralateral side of the lesion. Bilateral increased glycolytic metabolism and an inflammatory muscle profile were detected in dyskinetic rats. There was increased Fos-B expression in the spinal nucleus of lesioned rats and in the motor and facial nucleus in L-DOPA-induced dyskinetic rats in the contralateral side of the lesion. Glial cells were increased in the facial nucleus on the contralateral side of the lesion. Overall, spinal trigeminal nucleus activation may be associated with orofacial sensorial impairment in Parkinsonian rats, while a fatigue profile on LPMs is suggested in L-DOPA-induced dyskinesia when the motor and facial nucleus are activated. Full article

With its pathophysiological characteristics strongly similar to patients with tardive dyskinesia (TD), haloperidol (HP)-induced neurotoxicity and orofacial dyskinesia (OD) in animal models have long been used to study human TD. This study aimed to explore the potential protective effects of betaine (BT), a vital biochemical compound present in plants, microorganisms, animals, and various dietary sources. The study focused on investigating the impact of BT on haloperidol (HP)-induced orofacial dyskinesia (OD) in rats, as well as the underlying neuroprotective mechanisms. To induce the development of OD, which is characterized by increased vacuous chewing movement (VCM) and tongue protrusion (TP), rats were administered HP (1 mg/kg i.p.) for 21 consecutive days. BT was administered intraperitoneally (i.p.) at doses of 30 and 100 mg/kg, 60 min later, for 21 successive days. On the 21st day, after evaluating OD behavior, the rats were sacrificed, and various measurements were taken to assess the nitrosative and oxidative status, antioxidant capacity, mitochondrial function, neuroinflammation, and apoptotic markers in the striatum. The results demonstrated that (1) HP induced OD development, and (2) BT was found to prevent most of the HP-induced OD; decrease oxidative stress levels; increase anti-oxidation power; prevent mitochondrial dysfunction; and reduce the levels of neuroinflammatory and apoptotic markers in the striatum. Our results demonstrate that the neuroprotective effects of BT against HP-induced OD are credited to its antioxidant prevention of mitochondrial dysfunction, anti-neuroinflammatory effects, and anti-apoptotic effects, suggesting that BT may be a novel therapeutic candidate in delaying or treating human TD in clinical settings. However, further studies will be warranted to extrapolate preclinical findings into clinical studies for a better understanding of the role of BT. Full article

Background: Tardive dyskinesia (TD) is an extrapyramidal side effect of the long-term use of antipsychotics. In the present study, the role of glutamatergic system genes in the pathogenesis of total TD, as well as two phenotypic forms, orofacial TD and limb-truncal TD, was studied. Methods: A set of 46 SNPs of the glutamatergic system genes (GRIN2A, GRIN2B, GRIK4, GRM3, GRM7, GRM8, SLC1A2, SLC1A3, SLC17A7) was studied in a population of 704 Caucasian patients with schizophrenia. Genotyping was performed using the MassARRAY Analyzer 4 (Agena Bioscience™). Logistic regression analysis was performed to test for the association of TD with the SNPs while adjusting for confounders. Results: No statistically significant associations between the SNPs and TD were found after adjusting for multiple testing. Since three SNPs of the SLC1A2 gene demonstrated nominally significant associations, we carried out a haplotype analysis for these SNPs. This analysis identified a risk haplotype for TD comprising CAT alleles of the SLC1A2 gene SNPs rs1042113, rs10768121, and rs12361171. Nominally significant associations were identified for SLC1A3 rs2229894 and orofacial TD, as well as for GRIN2A rs7192557 and limb-truncal TD. Conclusions: Genes encoding for mGlu3, EAAT2, and EAAT1 may be involved in the development of TD in schizophrenia patients. Full article

Background: We report the case of a patient presenting with orofacial tardive dyskinesia (TD), following administration of a first-generation antipsychotic (Loxapine). Intervention: Four weeks of repeated sessions of mindfulness-based cognitive therapy (MBCT) and mindfulness-based stress reduction (MBSR) protocols were administered, with TD hetero-quantified before and during each session via the Abnormal Involuntary Movement Scale (AIMS). Results: The dyskinesia ameliorated quantitatively and qualitatively (1) during each session, and (2) at resting conditions in the long term. During some sessions, after which patients’ compliance was auto-evaluated as maximal, complete arrest of the TD was observed. Hypothesis and Conclusion: We suggest mindfulness meditation as a novel adjunctive therapeutic approach for tardive dyskinesia, and invite for further clinical and neurological investigations. Full article

Background: Parkinsonism is a common side-effect of antipsychotic drugs especially in older adults, who also present with a higher frequency of neurodegenerative disorders like Idiopathic Parkinson’s disease (IPD). Distinguishing between antipsychotic-induced parkinsonism (AIP) and IPD is challenging due to clinical similarities. Up to 20% of older adults may suffer from persisting parkinsonism months after discontinuation of antipsychotics, suggesting underlying neurodegeneration. A review of the literature on AIP in older adults is presented, focusing on epidemiology, clinical aspects, and management. Methods: A literature search was undertaken on EMBASE, MEDLINE and PsycINFO, for articles on parkinsonism induced by antipsychotic drugs or other dopamine 2 receptor antagonists in subjects aged 65 or older. Results: AIP in older adults is the second most common cause of parkinsonism after IPD. Older age, female gender, exposure to high-potency first generation antipsychotics, and antipsychotic dosage are the main risk factors. The clinical presentation of AIP resembles that of IPD, but is more symmetrical, affects upper limbs more, and tends to have associated motor phenomena such as orofacial dyskinesias and akathisia. Presence of olfactory dysfunction in AIP suggests neurodegeneration. Imaging of striatal dopamine transporters is widely used in IPD diagnosis and could help to distinguish it from AIP. There is little evidence base for recommending pharmacological interventions for AIP, the best options being dose-reduction/withdrawal, or switching to a second-generation drug. Conclusions: AIP is a common occurrence in older adults and it is possible to differentiate it from IPD. Further research is needed into its pathophysiology and on its treatment. Full article

Dopaminergic medication for Parkinson’s disease is associated with troubling dystonia and dyskinesia and, in rodents, dopaminergic agonists likewise induce a variety of orofacial motor responses, certain of which are mimicked by serotonin2C (5-HT_2C) receptor agonists. However, the neural substrates underlying these communalities and their interrelationship remain unclear. In Sprague-Dawley rats, the dopaminergic agonist, apomorphine (0.03–0.3 mg/kg) and the preferential D2/3 receptor agonist quinpirole (0.2–0.5 mg/kg), induced purposeless oral movements (chewing, jaw tremor, tongue darting). The 5-HT_2C receptor antagonist 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxyl]-5-pyridyl]carbamoyl]-6-trifluoromethylindone (SB 243213) (1 mg/kg) reduced the oral responses elicited by specific doses of both agonists (0.1 mg/kg apomorphine; 0.5 mg/kg quinpirole). After having confirmed that the oral bouts induced by quinpirole 0.5 mg/kg were blocked by another 5-HT_2C antagonist (6-chloro-5-methyl-1-[6-(2-methylpiridin-3-yloxy)pyridine-3-yl carbamoyl] indoline (SB 242084), 1 mg/kg), we mapped the changes in neuronal activity in numerous sub-territories of the basal ganglia using c-Fos expression. We found a marked increase of c-Fos expression in the subthalamic nucleus (STN) in combining quinpirole (0.5 mg/kg) with either SB 243213 or SB 242084. In a parallel set of electrophysiological experiments, the same combination of SB 243213/quinpirole produced an irregular pattern of discharge and an increase in the firing rate of STN neurons. Finally, it was shown that upon the electrical stimulation of the anterior cingulate cortex, quinpirole (0.5 mg/kg) increased the response of substantia nigra pars reticulata neurons corresponding to activation of the “hyperdirect” (cortico-subthalamonigral) pathway. This effect of quinpirole was abolished by the two 5-HT_2C antagonists. Collectively, these results suggest that induction of orofacial motor responses by D2/3 receptor stimulation involves 5-HT_2C receptor-mediated activation of the STN by recruitment of the hyperdirect (cortico-subthalamonigral) pathway. Full article

Chorea acanthocytosis (ChAc), an ultra-rare devastating neurodegenerative disease, is caused by mutations in the VPS13A gene, which encodes for the protein chorein. Affected patients suffer from chorea, orofacial dyskinesia, epilepsy, parkinsonism as well as peripheral neuropathy. Although medium spinal neurons of the striatum are mainly affected, other regions are impaired as well over the course of the disease. Animal studies as well as studies on human erythrocytes suggest Lyn-kinase inhibition as valuable novel opportunity to treat ChAc. In order to investigate the peripheral neuropathy aspect, we analyzed induced pluripotent stem cell derived midbrain/hindbrain cell cultures from ChAc patients in vitro. We observed dendritic microtubule fragmentation. Furthermore, by using in vitro live cell imaging, we found a reduction in the number of lysosomes and mitochondria, shortened mitochondria, an increase in retrograde transport and hyperpolarization as measured with the fluorescent probe JC-1. Deep phenotyping pointed towards a proximal axonal deterioration as the primary axonal disease phenotype. Interestingly, pharmacological interventions, which proved to be successful in different models of ChAc, were ineffective in treating the observed axonal phenotypes. Our data suggests that treatment of this multifaceted disease might be cell type and/or neuronal subtype specific, and thus necessitates precision medicine in this ultra-rare disease. Full article

28 patients in an orthodontic practice who demonstrated both characteristic malocclusion forms with deficiency in the sagittal, transverse and vertical dimensions and orofacial dyskinesia of the inner and outer circles were divided according to clinical criteria into two therapy groups within the framework of a pilot study. One group was treated exclusively with myofunctional therapy, the other with myofunctional therapy and orthodontic appliances (for example activators). Specific examination and goal parameters were documented at the commencement and the conclusion of therapy. Full article

Oral myofunctional therapy was found to be successful, In a group of 75 patients, ages six to 22 all with anterior open bites. Seventeen of 19 who lisped before therapy eliminated the lisp. Upper respiratory system allergies were eliminated In nine of 11 patients. A combination of myofunctional therapy and orthodontic treatment was more successful in correcting lip resting posture than was therapy alone. Lip and tongue resting postures, along with swallowing patterns, were corrected to a highly significant degree. Full article