Protective role of endocannabinoid signaling in an animal model of haloperidol-induced tardive dyskinesia.

Tardive dyskinesia (TD) is a side effect associated with the long-term use of certain antipsychotics. Considering the modulatory role of the endocannabinoid system upon dopaminergic neurotransmission, the present study tested the hypothesis that increasing endocannabinoid (anandamide and 2-arachidonoylglycerol) levels attenuates haloperidol-induced TD (vacuous chewing movements, VCMs) in male Wistar rats. The animals received administration of chronic haloperidol (38 mg/kg; 29 days) followed by acute FAAH (URB597, 0.1-0.5 mg/kg) or MAGL (JZL184, 1-10 mg/kg) inhibitors before VCM quantification. The underlying mechanisms were evaluated by pre-treatments with a CB1 receptor antagonist (AM251, 1 mg/kg) or a TRPV1 channel blocker (SB366791, 1 mg/kg). Moreover, CB1 receptor expression was evaluated in the striatum of high-VCM animals. As expected, haloperidol induced VCMs only in a subset of rats. Either FAAH or MAGL inhibition reduced VCMs. These effects were prevented by CB1 receptor antagonism, but not by TRPV1 blockage. Remarkably, CB1 receptor expression was increased high-VCM rats, with a positive correlation between the levels of CB1 expression and the number of VCMs. In conclusion, increasing endocannabinoid levels results in CB1 receptor-mediated protection against haloperidol-induced TD in rats. The increased CB1 receptor expression after chronic haloperidol treatment suggests a counter-regulatory protective mechanism.

Naringin Ameliorates Haloperidol-Induced Neurotoxicity and Orofacial Dyskinesia in a Rat Model of Human Tardive Dyskinesia.

Animal models of haloperidol (HAL)-induced neurotoxicity and orofacial dyskinesia (OD) have long been used to study human tardive dyskinesia (TD). Similar to patients with TD, these models show strong pathophysiological characteristics such as striatal oxidative stress and neural cytoarchitecture alteration. Naringin (NAR), a bioflavonoid commonly found in citrus fruits, has potent antioxidative, anti-inflammatory, antiapoptotic, and neuroprotective properties. The present study evaluated the potential protective effects of NAR against HAL-induced OD in rats and the neuroprotective mechanisms underlying these effects. HAL treatment (1 mg/kg i.p. for 21 successive days) induced OD development, characterized by increased vacuous chewing movement (VCM) and tongue protrusion (TP), which were recorded on the 7th, 14th, and 21st day of drug treatment. NAR (30, 100, and 300 mg/kg) was administered orally 60 min before HAL injection for 21 successive days. On the 21st day, after behavioral testing, the rats were sacrificed, and the nitrosative and oxidative status, antioxidation power, neurotransmitter levels, neuroinflammation, and apoptotic markers in the striatum were measured. HAL induced OD development, with significant increases in the frequency of VCM and TP. NAR treatment (100 and 300 mg/kg) prevented HAL-induced OD significantly. Additionally, NAR treatment reduced the HAL-induced nitric oxide and lipid peroxide production, increased the antioxidation power and neurotransmitter levels in the striatum, and significantly reduced the levels of neuroinflammatory and apoptotic markers. Our results first demonstrate the neuroprotective effects of NAR against HAL-induced OD, suggesting that NAR may help in delaying or treating human TD in clinical settings.

Tardive neurotoxicity of anticholinergic drugs: A review.

The cholinergic system is a complex neurotransmitter system with functional involvement at multiple levels of the nervous system including the cerebral cortex, spinal cord, autonomic nervous system, and neuromuscular junction. Anticholinergic medications are among the most prescribed medications, making up one-third to one-half of all medications prescribed for seniors. Recent evidence has linked long-term use of anticholinergic medications and dementia. Emerging evidence implicates the cholinergic system in the regulation of cerebral vasculature as well as neuroinflammation, suggesting that anticholinergic medications may contribute to absolute risk and progression of neurodegenerative diseases. In this review, we explore the involvement of the cholinergic system in various neurodegenerative diseases and the possible detrimental effects of anticholinergic medications on the onset and progression of these disorders. We identified references by searching the PubMed and Cochrane database between January 1990 and September 2019 for English-language animal and human studies including randomized clinical trials (RCTs), meta-analyses, systematic reviews, and observational studies. In addition, we conducted a manual search of reference lists from retrieved studies. Long-term anticholinergic medication exposure may have detrimental consequences beyond well-documented short-term cognitive effects, through a variety of mechanisms either directly impacting cholinergic neurotransmission or through receptors expressed on the vasculature or immune cells, providing a pathophysiological framework for complex interactions across the entire neuroaxis.

A preliminary exome sequence in three patients with tardive dystonia.

Tardive dystonia is one of the most serious adverse events that can be caused by antipsychotic treatment, but few studies have examined the etiology of tardive dystonia, and no genetic study using a next-generation sequencing technique has been performed to date. We conducted exome sequencing in three subjects with severe tardive dystonia. We analyzed the results focusing on candidate genes of primary dystonia, for example, TOR1A, GCH1, TH, THAP1, and SGCE. There were no single-nucleotide polymorphisms of these dystonia genes that were commonly shared among our subjects. Instead, the results revealed the presence of rare mutations (minor allele frequency <0.01) on the ZNF806 and SART3 genes in all three patients. This is the first study to analyze whole-exonic regions of the genomes of patients with tardive dystonia. These results were only preliminary, but they suggest that subjects presenting with tardive dystonia induced by antipsychotic treatment can have a genetic predisposition to tardive dystonia.

Tardive dyskinesia is associated with altered putamen Akt/GSK-3ß signaling in nonhuman primates.

BACKGROUND: Tardive dyskinesia is a delayed and potentially irreversible motor complication arising from chronic exposure to antipsychotic drugs. Interaction of antipsychotic drugs with G protein-coupled receptors triggers multiple intracellular events. Nevertheless, signaling pathways that might be associated with chronic unwanted effects of antipsychotic drugs remain elusive. In this study, we aimed to better understand kinase signaling associated with the expression of tardive dyskinesia in nonhuman primates. METHODS: We exposed capuchin monkeys to prolonged haloperidol (n = 10) or clozapine (n = 6) treatments. Untreated animals were used as controls (n = 6). Half of haloperidol-treated animals (5) developed mild tardive dyskinesia similar to that found in humans. Using Western blots and immunochemistry, we measured putamen total and phosphorylated protein kinase levels associated with canonical and noncanonical signaling cascades of G protein-coupled receptors. RESULTS: Antipsychotic drugs enhanced pDARPP-32 and pERK1/2, but no difference ws observed in phosphoprotein kinase levels between dyskinetic and nondyskinetic monkeys. On the other hand, comparison of kinase levels between haloperidol-treated dyskinetic and nondyskinetic monkeys indicated that dyskinetic animals had lower GRK6 and ß-arrestin2 levels. Levels of pAkt and pGSK-3ß were also reduced, but only haloperidol-treated monkeys that developed tardive dyskinesia had reduced pGSK-3ß levels, whereas pAkt levels in dyskinetic animals positively correlated with dyskinetic scores. Interestingly, double immunofluorescence labeling showed that putamen dopamine D3 receptor levels were upregulated and that D3/pAkt colocalization was enriched in haloperidol-treated animals displaying tardive dyskinesia. CONCLUSIONS: Our results suggest that upregulation of putamen dopamine D3 receptor and alterations along the noncanonical GRK6/ß-arrestin2/Akt/GSK-3ß molecular cascade are associated with the development of tardive dyskinesia in nonhuman primates. © 2019 International Parkinson and Movement Disorder Society.

Impact of Deuterium Substitution on the Pharmacokinetics of Pharmaceuticals.

OBJECTIVE: Stable heavy isotopes of hydrogen, carbon, and other elements have been incorporated into drug molecules, largely as tracers for quantitation during the drug development process. Studies involving the human use of drugs labeled with deuterium suggest that these compounds may offer some advantages when compared with their nondeuterated counterparts. Deuteration has gained attention because of its potential to affect the pharmacokinetic and metabolic profiles of drugs. Deutetrabenazine (Austedo, Teva Pharmaceutical Industries, Ltd) is the first deuterated drug to receive Food and Drug Administration approval. This deuterated form of the drug tetrabenazine is indicated for the treatment of chorea associated with Huntington's disease as well as tardive dyskinesia. Ongoing clinical trials suggest that a number of other deuterated compounds are being evaluated for the treatment of human diseases and not merely as research tools. DATA SOURCES: A search of the MEDLINE (1946 to present) database was undertaken using the Ovid interface. The search was conducted using the heading deuterium and then limited to Administration & Dosage, Adverse Effects, Pharmacokinetics, Pharmacology, Poisoning, Therapeutic Use, and Toxicity. STUDY SELECTION AND DATA EXTRACTION: All articles were reviewed and those with human information were included. Review articles were likewise interrogated for additional published human data. CONCLUSIONS: Deuterated compounds may, in some cases, offer advantages over nondeuterated forms, often through alterations in clearance. Deuteration may also redirect metabolic pathways in directions that reduce toxicities. The approval of additional deuterated compounds may soon follow. Clinicians will need to be familiar with the dosing, efficacy, potential side effects, and unique metabolic profiles of these new entities.

Tardive dyskinesia: Who gets it and why.

Tardive dyskinesia (TD) is a potentially permanent movement disorder resulting from chronic use of dopamine receptor blocking agents (DRBA). Identified risk factors include the type of antipsychotic agent, being greater for those of first generation antipsychotics (FGA), the duration of illness and cumulative dose of DRBA and advanced age. Female sex and African and Caucasian ethnicity are additional potential risk factors. Because only a subset of people taking DRBA's develops TD, genetics may play a role. Susceptibility gene candidates include those involved in DRBA metabolism and the targets or receptors of DRBA's. Although met with conflicting data, the following genes may be involved with TD development: the cytochrome P450 gene CYP2D6, involved with metabolism of most antipsychotics, Dopamine D2 and D3 receptor genes, serotonin 2A and 2C receptor genes, vesicular monoamine transporter 2 (VMAT 2) gene, involved with intracellular neurotransmitter packaging, and the manganese superoxide dismutase (MnSOD) gene, an antioxidant enzyme. Heparan sulfate proteoglycan 2 (HSPG 2) gene is another potential gene involved with development of TD. The pathogenesis of TD is unknown, however there are three main theories proposed: dopamine receptor supersensitivity resulting from chronic dopamine receptor blockade, oxidative stress and maladaptive synaptic plasticity each of which is discussed further in this article. Tardive dyskinesia (TD) is a potentially permanent and disabling adverse effect from certain medications. By definition TD is the insidious onset of rhythmic, repetitive, stereotypic movements of the face, mouth and tongue, often with involvement of the trunk and extremities that occur as a result of dopamine receptor blocking agents (DRBA) [1]. The term tardive refers to the delayed onset of the disorder. The mean prevalence of TD is estimated to be 25.3% in psychiatric patients taking antipsychotics [2]. Compared to the number of people taking these drugs, TD represents a minority. TD is a potentially permanent condition; stopping the offending agent does not always alleviate the condition. Therefore, prevention of TD by avoiding DRBA's if at all possible is ideal. However, there is no apparent way to predict who will develop TD and there are some cases in which DRBA's are necessary for treatment of chronic conditions. As TD has been present since the development of DRBA's, possible risk factors for its development have been studied. Solmi et al. (2018) [3] have written a comprehensive review on this subject.

VMAT2 inhibitors for the treatment of tardive dyskinesia.

Tardive dyskinesia (TD) is an often disabling hyperkinetic movement disorder caused by exposure to dopamine receptor blocking agents. Although initially thought to most commonly occur with typical antipsychotics, the incidence is likely similar with atypical antipsychotics and antiemetics such as metoclopramide. Increased prescribing of these agents as well as low rates of remission have contributed to a rising prevalence of TD. Although this condition was described nearly 60 years ago, it is only within the past year that two novel therapeutic agents were FDA approved. Characterization of the VMAT2 inhibitor tetrabenazine, which was identified as a therapeutic agent for TD in older clinical trials, has yielded two distinct pharmacologic strategies to optimize response. The first strategy, used to create deutetrabenazine, employed deuterization of tetrabenazine to stabilize the pharmacokinetics and eliminate high peak plasma levels. The second strategy was the creation of a prodrug, valbenazine, for the two most active isoforms of tetrabenazine that also resulted in more stable pharmacokinetics and eliminated peak plasma levels. Both agents have been demonstrated to be effective and safe for the treatment of TD in multicenter, controlled trials and their development has led to a resurgence of interest in the characterization and treatment of this movement disorder.

Mechanism of action of vesicular monoamine transporter 2 (VMAT2) inhibitors in tardive dyskinesia: reducing dopamine leads to less "go" and more "stop" from the motor striatum for robust therapeutic effects.

Tardive dyskinesia can now be successfully treated by inhibiting the vesicular monoamine transporter type 2 (VMAT2).

Angiotensin II type 1/adenosine A 2A receptor oligomers: a novel target for tardive dyskinesia.

Tardive dyskinesia (TD) is a serious motor side effect that may appear after long-term treatment with neuroleptics and mostly mediated by dopamine D2 receptors (D2Rs). Striatal D2R functioning may be finely regulated by either adenosine A2A receptor (A2AR) or angiotensin receptor type 1 (AT1R) through putative receptor heteromers. Here, we examined whether A2AR and AT1R may oligomerize in the striatum to synergistically modulate dopaminergic transmission. First, by using bioluminescence resonance energy transfer, we demonstrated a physical AT1R-A2AR interaction in cultured cells. Interestingly, by protein-protein docking and molecular dynamics simulations, we described that a stable heterotetrameric interaction may exist between AT1R and A2AR bound to antagonists (i.e. losartan and istradefylline, respectively). Accordingly, we subsequently ascertained the existence of AT1R/A2AR heteromers in the striatum by proximity ligation in situ assay. Finally, we took advantage of a TD animal model, namely the reserpine-induced vacuous chewing movement (VCM), to evaluate a novel multimodal pharmacological TD treatment approach based on targeting the AT1R/A2AR complex. Thus, reserpinized mice were co-treated with sub-effective losartan and istradefylline doses, which prompted a synergistic reduction in VCM. Overall, our results demonstrated the existence of striatal AT1R/A2AR oligomers with potential usefulness for the therapeutic management of TD.

Antioxidant effects of rice bran oil mitigate repeated haloperidol-induced tardive dyskinesia in male rats.

Tardive dyskinesia (TD) is associated with the use of antipsychotic drugs such as D2 antagonist haloperidol (HP). The chronic use of HP is involved in the causation of free radicals and/or oxidative stress. In view of the nootropic, anti-anxiety, anti-inflammatory-like effects of rice bran oil (RBO) in a variety of investigations, we assessed the protective properties of RBO on HP-induced TD and neurochemical alteration. Rats treated with HP orally at a dose of 0.2 mg/kg/day for a period of 5 weeks developed VCMs which increased progressively as the treatment continued for 5 weeks. Co-administration of RBO by oral tubes at a dose of 0.4 ml/day prevented the induction of HP-induced VCMs. Repeated administration of HP increases the turnover of dopamine metabolism in the striatum. Conversely animals treated with HP + RBO decrease the metabolism of DA than water + HP treated animals. Striatal, malondieldehyde (MDA), hydrogen peroxide (H2O2) and antioxidant enzyme superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were also determined. It is suggested that beneficial role of RBO in attenuation of HP-induced TD. The results therefore recommended that supplementation of RBO may be useful in the HP-induced TD. The findings have also potential implication in the treatment of schizophrenia and motor disorders.

Behavioral and neurochemical effects of alpha lipoic acid associated with omega-3 in tardive dyskinesia induced by chronic haloperidol in rats.

Tardive dyskinesia (TD) is characterized by involuntary movements of the lower portion of the face being related to typical antipsychotic therapy. TD is associated with the oxidative imbalance in the basal ganglia. Lipoic acid (LA) and omega-3 (ω-3) are antioxidants acting as enzyme cofactors, regenerating antioxidant enzymes. This study aimed to investigate behavioral and neurochemical effects of supplementation with LA (100 mg/kg) and ω-3 (1 g/kg) in the treatment of TD induced by chronic use of haloperidol (HAL) (1 mg/kg) in rats. Wistar male rats were used, weighing between 180-200 g. The animals were treated chronically (31 days) with LA alone or associated with HAL or ω-3. Motor behavior was assessed by open-field test, the catalepsy test, and evaluation of orofacial dyskinesia. Oxidative stress was accessed by determination of lipid peroxidation and concentration of nitrite. LA and ω-3 alone or associated caused an improvement in motor performance by increasing locomotor activity in the open-field test and decreased the permanence time on the bar in the catalepsy test and decreased the orofacial dyskinesia. LA and ω-3 showed antioxidant effects, decreasing lipid peroxidation and nitrite levels. Thus, the use of LA associated with ω-3 reduced the extrapyramidal effects produced by chronic use of HAL.

Dopamine depleters in the treatment of hyperkinetic movement disorders.

INTRODUCTION: Abnormal involuntary movements often improve in response to anti-dopaminergic drugs. In contrast to classic neuroleptics that block dopamine receptors, drugs that deplete presynaptic dopamine by blocking vesicular monoamine transporter type 2 (VMAT2) seem to be safer and have little or no risk of tardive dyskinesia. This is one reason why there has been a recent emergence of novel VMAT2 inhibitors. Areas covered: Since the approval of tetrabenazine, the classic VMAT2 inhibitor, in the treatment of chorea associated with Huntington disease (HD), other VMAT2 inhibitors (e.g. deutetrabenazine and valbenazine) have been studied in the treatment of HD-related chorea, tardive dyskinesia and tics associated with Tourette syndrome. This review, based largely on a detailed search of PubMed, will summarize the pharmacology and clinical experience with the various VMAT2 inhibitors. Expert commentary: Because of differences in pharmacology and pharmacokinetics these new VMAT2 inhibitors promise to be at least as effective as tetrabenazine but with a lower risk of adverse effects, such as sedation, insomnia, depression, parkinsonism, and akathisia.

Ginkgo biloba and vitamin E ameliorate haloperidol-induced vacuous chewingmovement and brain-derived neurotrophic factor expression in a rat tardive dyskinesia model.

Neurodegeneration may be involved in the development of tardive dyskinesia (TD), and low levels of brain-derived neurotrophic factor (BDNF) may play a role. Ginkgo biloba (EGb761), a potent antioxidant, may have neuroprotective effects. We hypothesized that there would be decreased BDNF expression in TD, but that treatment with EGb761 would increase BDNF expression and reduce TD manifestations in a rat model. Forty rats were treated with haloperidol (2mg/kg/day via intraperitoneal injections) for 5weeks. EGb761 (50mg/kg/day) and vitamin E (20mg/kg/day) were then administered by oral gavage for another 5weeks, and we compared the effects of treatment with EGb761 or vitamin E on haloperidol-induced vacuous chewing movements (VCMs) and BDNF expression in four brain regions: prefrontal cortex (PFC), striatum (ST), substantia nigra (SNR), and globus pallidus (GP). Our results showed that haloperidol administration led to a progressive increase in VCMs, but both EGb761 and vitamin E significantly decreased VCMs. Haloperidol also decreased BDNF expression in all four brain regions, but both EGb761 and vitamin E administration significantly increased BDNF expression. Our results showed that both EGb761 and VE treatments exerted similar positive effects in a rat model of TD and increased BDNF expression levels in the four tested brain regions, suggesting that both EGb761 and vitamin E improve TD symptoms, possibly by enhancing BDNF in the brain and/or via their free radical-scavenging actions.

Association study of MiRSNPs with schizophrenia, tardive dyskinesia and cognition.

MicroRNAs (miRNAs) bind to 3'UTRs of genes and negatively regulate their expression. With ~50% of miRNAs expressing in the brain, they play an important role in neuronal development, plasticity, cognition and neurological disorders. Conserved miRNA targets are present in >60% genes in humans and are under evolutionary pressure to maintain pairing with miRNA. However, such binding may be affected by genetic variant(s) in the target sites (MiRSNPs), thereby altering gene expression. Differential expression of a large number of genes in postmortem brains of schizophrenia (SZ) patients compared to controls has been documented. Thus studying the role of MiRSNPs which are underinvestigated in SZ becomes attractive. We systematically selected 35 MiRSNPs with predicted functional relevance in 3'UTRs of genes shown previously to be associated with SZ, genotyped and tested their association with disease, using independent discovery and replication samples (total n=1017 cases; n=1073 controls). We also explored genetic associations with two sets of quantitative traits, namely tardive dyskinesia (TD) and cognitive functions disrupted in SZ in subsets of the study cohort. In the primary analysis, a significant association of MiRSNP rs7430 at PPP3CC was observed with SZ in the discovery and the replication samples [discovery: P=0.01; OR (95% CI) 1.24 (1.04-1.48); replication: P=0.03; OR (95% CI) 1.20 (1.02-1.43)]. In the exploratory analyses, five SNPs were nominally associated with TD (P values 0.04-0.004). Separately, 12 SNPs were associated with one or more of the eight cognitive domains (P values 0.05-0.003). These associations, particularly the SNP at PPP3CC merit further investigations.

Harpagophytum Procumbens Ethyl Acetate Fraction Reduces Fluphenazine-Induced Vacuous Chewing Movements and Oxidative Stress in Rat Brain.

Long-term treatment with fluphenazine is associated with manifestation of extrapyramidal side effects, such as tardive dyskinesia. The molecular mechanisms related to the pathophysiology of TD remain unclear, and several hypotheses, including a role for oxidative stress, have been proposed. Harpagophytum procumbens is an herbal medicine used mainly due to anti-inflammatory effects, but it also exhibits antioxidant effects. We investigated the effect of ethyl acetate fraction of H. procumbens (EAF HP) in fluphenazine-induced orofacial dyskinesia by evaluating behavioral parameters at different times (vacuous chewing movements (VCM's) and locomotor and exploratory activity), biochemical serological analyses, and biochemical markers of oxidative stress of the liver, kidney, cortex, and striatum. Chronic administration of fluphenazine (25 mg/kg, intramuscular (i.m) significantly increased the VCMs at all analyzed times (2, 7, 14, and 21 days), and this was inhibited by EAF HP (especially at a dose of 30 mg/kg). Fluphenazine decreased locomotion and exploratory activity, and EAF HP did not improve this decrease. Fluphenazine induced oxidative damage, as identified by changes in catalase activity and ROS levels in the cortex and striatum, which was reduced by EAF HP, especially in the striatum. In the cortex, EAF HP was protective against fluphenazine-induced changes in catalase activity but not against the increase in ROS level. Furthermore, EAF HP was shown to be safe, since affected serum biochemical parameters or parameters of oxidative stress in the liver and kidney. These findings suggest that the H. procumbens is a promising therapeutic agent for the treatment of involuntary oral movements.

Co-treatment with imipramine averted haloperidol-instigated tardive dyskinesia: Association with serotonin in brain regions.

Outcome of imipramine (IMI) treatment was scrutinized on progression of haloperidol instigated tardive dyskinesia (TD). 0.2 mg/kg/rat dosage of haloperidol provided orally to rats for 2 weeks enhanced vacuous chewing movements that escalated when the process proceeded for 5 weeks. Following 2 weeks co-injection 5 mg/kg dosage of IMI was diminished haloperidol-instigated VCMs and fully averted following five weeks. The potency of 8-OH-DPAT-instigated locomotor activity exhibited higher in saline+haloperidol treated rats while not observed in IMI+ haloperidol treated rats. 8-OH-DPAT-instigated low 5-hydroxytryptamine (5-HT; serotonin) metabolism was higher in saline+ haloperidol treated rats when compare to IMI+ haloperidol treated rats in both regions of brain (striatum and midbrain). It is recommended that IMI possibly competent in averting TD, in cases receiving treatment to antipsychotics.