Humanized CYP2C19 transgenic mouse as an animal model of cerebellar ataxia

Background: Animal models are essential for understanding etiology and pathophysiology of movement disorders. Previously, we have found that mice transgenic for the human CYP2C19 gene, expressed in the liver and developing brain, exhibit altered neurodevelopment associated with impairments of their motor function and emotionality. Objectives: To characterize motoric phenotype of the CYP2C19 transgenic mice and validate its usefulness as an animal model of ataxia. Methods: The rotarod and beam-walking tests were utilized to quantify the functional alterations induced by motoric phenotype. Dopaminergic system was assessed by tyrosine hydroxylase immunohistochemistry and by chromatographic quantification of the whole-brain dopamine levels. Beam-walking test was also repeated after the treatment with the dopamine receptor antagonists, ecopipam and raclopride. The volumes of 20 brain regions in the CYP2C19 transgenic mice and controls were quantified by 9.4T gadolinium-enhanced postmortem structural neuroimaging. Results: CYP2C19 transgenic mice were found to exhibit abnormal, unilateral ataxia-like gait, clasping reflex and 5.6-fold more paw-slips using the beam-walking test (p<0.0001, n=89); the phenotype was more pronounced in younger animals. Hyperdopaminergism was observed in the CYP2C19 mice; however, the motoric impairment was not ameliorated by dopamine receptor antagonists and there was also no midbrain dopamine neuron loss in CYP2C19 mice. However, in these mice, cerebellar volume was drastically decreased (-11.8% [95%CI: -14.7, -9.0], q<0.0001, n=59), whereas a moderate decrease in hippocampal volume was observed (-4.2% [95%CI: -6.4%, -1.9%], q=0.015, n=59). Conclusions: Humanized CYP2C19 transgenic mice exhibit altered motoric function and functional motoric impairments; this phenotype is likely caused by an aberrant cerebellar development.

Effects of acute and repeated administration of the selective M4 PAM VU0152099 on cocaine vs. food choice in male rats

Ligands that stimulate muscarinic acetylcholine receptors 1 and 4 (M1, M4) have shown promising effects as putative pharmacotherapy for cocaine use disorder in rodent assays. We have previously shown reductions in cocaine effects with acute M4 stimulation, as well as long-lasting, delayed, reductions in cocaine taking and cocaine seeking with combined M1/M4 receptor stimulation or with M1 stimulation alone. M4 stimulation opposes dopaminergic signaling acutely, but direct dopamine receptor antagonists have proved unhelpful in managing cocaine use disorder because they lose efficacy with long-term administration. It is therefore critical to determine whether M4 approaches themselves can remain effective with repeated or chronic dosing. We assessed the effects of repeated administration of the M4 positive allosteric modulator (PAM) VU0152099 in rats trained to choose between intravenous cocaine and a liquid food reinforcer, to obtain quantitative measurement of whether M4 stimulation could produce delayed and lasting reduction in cocaine taking. VU0152099 produced progressively augmenting suppression of cocaine choice and cocaine intake, but produced neither rebound nor lasting effects after treatment ended. To compare and contrast effects of M1 vs. M4 stimulation, we tested whether the M4 PAM VU0152100 suppressed cocaine self-administration in mice lacking CalDAG-GEFI signaling factor, required for M1- mediated suppression of cocaine self-administration. CalDAG-GEFI ablation had no effect on M4- mediated suppression of cocaine self-administration. These findings support the potential usefulness of M4 PAMs as pharmacotherapy to manage cocaine use disorder, alone or in combination with M1-selective ligands, and show that M1 and M4 stimulation modulate cocaine-taking behavior by distinct mechanisms.

An International Survey of Health Care Services Available to Patients With Tourette Syndrome

Objective: Tourette syndrome (TS) is a neuropsychiatric disorder that is highly associated with several comorbidities. Given the complex and multifaceted nature of TS, the condition is managed by a wide variety of practitioners in different disciplines. The goal of this study was to investigate health service delivery and care practices by clinicians who see TS patients across different geographic settings internationally.Methods: A comprehensive questionnaire was developed to assess clinical care resources for patients with TS and was sent to clinicians in Canada (CA), the United States (US), Europe (EU), and the United Kingdom (UK). Responses were compared quantitatively between geographic regions.Results: The majority of respondents, regardless of region, reported that fewer than 40% of their case-load are patients with tics. The accessibility of TS services varied among regions, as indicated by differences in wait times, telemedicine offerings, comorbidity management and the availability of behavioral therapies. First-line pharmacotherapy preferences varied among physicians in different geographical regions with CA respondents preferring alpha-2-adrenergic agonists and respondents from the UK and EU preferring dopamine receptor antagonists.Discussion: The results suggest that there is a scarcity of specialized TS clinics, potentially making access to services challenging, especially for patients newly diagnosed with TS. Differences in regional pharmacotherapeutic preferences are reflected in various published treatment guidelines in EU and North America. The lack of dedicated specialists and telemedicine availability, coupled with differences in comorbidity management, highlight the need for interprofessional care and holistic management to improve health care delivery to patients with TS.

Pan-Cancer analysis of clinical significance and associated molecular features of glycolysis

Background Tumor glycolysis acts as a major promoter of carcinogenesis and cancer progression. Given its complex mechanisms and interactions, a comprehensive analysis to reveal its clinical significance and molecular features is urgent. Materials and Methods Based on a well-established glycolysis gene expression signature, we quantified 8633 patients across different cancer types from The Cancer Genome Atlas (TCGA) and evaluated their prognostic associations. High tumor glycolytic activity correlated with inferior overall survival in pan-cancer patients (hazard ratio: 1.70, 95% confidence interval: 1.20–2.40, P = 0.003). The prognostic value of glycolysis was stable regardless of clinical parameters and correlated with molecular subtypes. The prognostic significance of glycolysis was validated using another three independent datasets. In addition, genome, transcriptome, and proteome profiles were utilized to characterize distinctive molecular features associated with glycolysis.Results Mechanistically, glycolysis fulfilled the fundamental needs of tumor proliferation in multiple ways. Exploration of the relationships between glycolysis and tumor infiltrating immune cells showed that glycolysis enabled immune evasion of tumor cells. Mammalian target of rapamycin inhibitors and dopamine receptor antagonists represent classes of compounds that can effectively reverse the glycolytic status of cancers.Conclusion Our study provides an in-depth molecular understanding of tumor glycolysis and may have practical implications for clinical cancer therapy.

Case Presentation: Iatrogenic Psychosis

Tardive dyskinesia (TD) is a neuromuscular disorder that can precipitate following the administration of dopamine receptor antagonists such as neuroleptics. Withdrawal-emergent dyskinesia (WE-D), a less recognized subtype of TD, can manifest shortly after abrupt cessation of antipsychotic use regardless of the neuroleptic subclass used. Super sensitivity psychosis is another possible symptom of acute withdrawal from neuroleptics that can occur alone or concomitant with WE-D. Because of their ever increasing off-label indications and attenuated extrapyramidal side effect profiles, atypical antipsychotics are becoming ubiquitous in both inpatient and outpatient settings, reflecting their utility. However, it is likely that this trend will also result in a greater prevalence of WE-D and super sensitivity psychosis. Clinicians without expertise in the utilization of neuroleptics are likely to misattribute withdrawal symptoms precipitated by abrupt cessation of antipsychotics with toxicity to these agents and erroneously withhold or delay their reinitiation, thereby exacerbating symptoms and inadvertently prolonging patient distress. This case report will illustrate the unique and perplexing presentation of WE-D and super sensitivity psychosis in an acute setting, and provide an effective diagnostic and treatment approach to resolving these conditions.

Peganum harmala and its Alkaloids as Dopamine Receptor Antagonists: in Silico Study

Peganum harmala is known to have active metabolites such as alkaloids, which can affect the central nervous system. One of the various alkaloids is thought to be related to their activity as dopamine receptor antagonists, which can be developed in the therapy of various neurological diseases. This study aims to determine the alkaloid from P. harmala, which has the highest potential as the dopamine receptor antagonist. The method used was molecular docking against dopamine receptors with risperidone as the reference ligand. The results showed that among the known alkaloids from P. harmala, dipegine, harmalanine, and harmalacinine showed the highest potency in terms of both free energy of binding and similarity of ligand-receptor interactions. The results of this investigation anticipate that some alkaloids from P. harmala have the potential as the dopamine receptor antagonist.

Diagnosis and Treatment of Neuroleptic Malignant Syndrome in the Intensive Care Unit: A Case Report

Neuroleptic malignant syndrome is a neurological emergency caused by dysregulation of dopaminergic neurotransmission. While it is typically characterized by muscle rigidity, fever and altered mental status, it may have a heterogeneous and non-specific presentation, leading to delays in diagnosis and treatment. Treatment involves cessation of dopamine-receptor antagonists and supportive measures, but in more severe cases, bromocriptine, dantrolene, benzodiazepines and/or electroconvulsive therapy should be considered. We present the case of a 66-year-old man with severe neuroleptic malignant syndrome, diagnosed due to need for continuous invasive ventilation in an Intensive Care Unit, after successful treatment for respiratory sepsis. The patient recovered after electroconvulsive therapy and administration of bromocriptine. This unusually severe case illustrates the need for a high level of suspicion for neuroleptic malignant syndrome in critically ill patients with malignant catatonic syndromes, allowing for an early diagnosis and potentially lifesavingtreatment.

Crushing deutetrabenazine for treatment of tardive dyskinesia in a patient with severe orofacial symptoms: A case report

Purpose Tardive dyskinesia (TD) is a hyperkinetic movement disorder that results from exposure to dopamine receptor antagonists and/or first- and second-generation antipsychotics. While cessation of the offending agent(s) through early detection is recommended, TD symptoms may be irreversible and require further treatment. Deutetrabenazine is approved by the Food and Drug Administration for treatment of persistent TD. Irreversible orofacial dyskinesia, a common affliction in TD, can progress to severe oropharyngeal dysphagia requiring alternate means of nutrition and medication delivery. Enteral administration of crushed deutetrabenazine has not been studied, and its use to treat TD in patients who cannot take medications by mouth has not been reported previously. Summary A 38-year-old female patient with a history of bipolar I disorder and TD secondary to atypical antipsychotic exposure developed worsening athetosis, hyperkinesia, and severe orofacial dyskinesia after initiation of ziprasidone. The patient had no improvement after discontinuation of atypical antipsychotics and required percutaneous endoscopic gastrostomy (PEG) placement for nutrition due to persistent aspiration and inability to tolerate oral nutrition. Despite a lack of information regarding administration of crushed deutetrabenazine tablets via PEG, that form of therapy was initiated and resulted in improvement of TD symptoms without noticeable adverse effects. Conclusion TD can result in significant orofacial dyskinesia with impaired delivery of needed medications and nutrition. We describe a case in which a patient with severe TD and orofacial dyskinesia experienced improvement of symptoms with use of crushed deutetrabenazine. Larger studies to further evaluate use of crushed deutetrabenazine for treatment of TD are needed.