Haloperidol‐Induced Preclinical Tardive Dyskinesia Model in Rats

Gúzen, Fausto Pierdoná; Cavalcanti, José Rodolfo Lopes de Paiva; Cavalcanti, Diogo Manuel Lopes de Paiva; Sales, Luma Gabrielle Praxedes de; Silva, Monalisa Stefany Martins da; Silva, Aline Naiara Azevedo da; Pinheiro, Francisco Irochima; Araújo, Dayane Pessoa de

doi:10.1002/cpns.68

Cited by 10 publications

(5 citation statements)

References 17 publications

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“…However, it is important to acknowledge that there are numerous concerns and debates surrounding the use of animal models for studying TD. Our findings regarding OD induced by HP align with those of other researchers and our own previous studies [3][4][5][6][7][10][11][12]. In our experiments, rats treated with HP for 21 consecutive days exhibited a significant increase in the frequency of VCM and TP, along with impairments in oxidative defense and mitochondrial function.…”

Section: Discussionsupporting

confidence: 92%

“…Not only do the characteristic features of HP-induced OD bear a strong resemblance to the symptoms of TD, but HP has also been implicated in the development of TD in humans. In rats, HP-induced changes in VCM (vacuous chewing movements) and TP (tongue protrusions) have proven to be a valuable model and an essential tool for identifying potential therapeutic agents for TD [3,4]. However, it is important to acknowledge that there are numerous concerns and debates surrounding the use of animal models for studying TD.…”

Section: Discussionmentioning

confidence: 99%

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Involvement of Antioxidant and Prevention of Mitochondrial Dysfunction, Anti-Neuroinflammatory Effect and Anti-Apoptotic Effect: Betaine Ameliorates Haloperidol-Induced Orofacial Dyskinesia in Rats

et al. 2023

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Involvement of Antioxidant and Prevention of Mitochondrial Dysfunction, Anti-Neuroinflammatory Effect and Anti-Apoptotic Effect: Betaine Ameliorates Haloperidol-Induced Orofacial Dyskinesia in Rats

et al. 2023

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“…The findings of Senousy et al 2022 [17] identified that the BCG vaccine inhibited the PI3k/Akt/mTOR signaling pathway and was involved in the improvement of mitochondrial function and restored the antioxidant levels in the 3-NPA-treated rat brain, which shows the neuroprotective potential of the BCG vaccine. Similarly, in our previous study, BCG reduced oxidative stress markers and improved locomotor activity in QA-induced HD rats [37]. Our study findings also indicate that the BCG vaccine has an antioxidant property, as it restored antioxidants (GSH, SOD, and catalase) and lowered oxido-nitrosative stress markers (MDA and nitrite) in the rat striatum, providing neuroprotection from oxidative stress generated by haloperidol.…”

Section: Discussionsupporting

confidence: 87%

“…Therefore, researchers have developed a haloperidol-induced rodent model that provides similar symptomatic conditions to TD [37].…”

Section: Discussionmentioning

confidence: 99%

Bacillus Calmette–Guérin Vaccine Attenuates Haloperidol-Induced TD-like Behavioral and Neurochemical Alteration in Experimental Rats

Yedke,

Upadhayay,

Singh

et al. 2023

Biomolecules

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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.

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“…The aforementioned PK characteristics are undoubtedly helpful for obtaining good PD results in vivo . VMAT2 inhibitors can inhibit the release of dopamine and reduce rat locomotor activity, which is used as a substitute index to evaluate the efficacy of VMAT2 inhibitors ( Grigoriadis et al, 2017 ; Guzen et al, 2019 ; Li et al, 2019 ). The multi-target activity screen of SpectrumScreen ® Panel (Eurofins screen) demonstrated that (+)-13e had no effects on dopamine receptors, serotonin receptors, adrenergic receptors, dopamine transporter, norepinephrine transporter, five serotonin transporter, and so on.…”

Section: Discussionmentioning

confidence: 99%

(+)-9-Trifluoroethoxy-α-Dihydrotetrabenazine as a Highly Potent Vesicular Monoamine Transporter 2 Inhibitor for Tardive Dyskinesia

Wang

Lin

et al. 2021

Front. Pharmacol.

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Valbenazine and deutetrabenazine are the only two therapeutic drugs approved for tardive dyskinesia based on blocking the action of vesicular monoamine transporter 2 (VMAT2). But there exist demethylated inactive metabolism at the nine position for both them resulting in low availability, and CYP2D6 plays a major role in this metabolism resulting in the genetic polymorphism issue. 9-trifluoroethoxy-dihydrotetrabenazine (13e) was identified as a promising lead compound for treating tardive dyskinesia. In this study, we separated 13e via chiral chromatography and acquired R,R,R-13e [(+)-13e] and S,S,S-13e [(−)-13e], and we investigated their VMAT2-inhibitory activity and examined the related pharmacodynamics and pharmacokinetics properties using in vitro and in vivo models (+)-13e displayed high affinity for VMAT2 (Ki = 1.48 nM) and strongly inhibited [3H]DA uptake (IC50 = 6.11 nM) in striatal synaptosomes. Conversely, its enantiomer was inactive. In vivo, (+)-13e decreased locomotion in rats in a dose-dependent manner. The treatment had faster, stronger, and longer-lasting effects than valbenazine at an equivalent dose. Mono-oxidation was the main metabolic pathway in the liver microsomes and in dog plasma after oral administration, and glucuronide conjugation of mono-oxidized and/or demethylated products and direct glucuronide conjugation were also major metabolic pathways in dog plasma. O-detrifluoroethylation of (+)-13e did not occur. Furthermore, CYP3A4 was identified as the primary isoenzyme responsible for mono-oxidation and demethylation metabolism, and CYP2C8 was a secondary isoenzyme (+)-13e displayed high permeability across the Caco-2 cell monolayer, and it was not a P-glycoprotein substrate as demonstrated by its high oral absolute bioavailability (75.9%) in dogs. Thus, our study findings highlighted the potential efficacy and safety of (+)-13e in the treatment of tardive dyskinesia. These results should promote its clinical development.

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Haloperidol‐Induced Preclinical Tardive Dyskinesia Model in Rats

Cited by 10 publications

References 17 publications

Involvement of Antioxidant and Prevention of Mitochondrial Dysfunction, Anti-Neuroinflammatory Effect and Anti-Apoptotic Effect: Betaine Ameliorates Haloperidol-Induced Orofacial Dyskinesia in Rats

Involvement of Antioxidant and Prevention of Mitochondrial Dysfunction, Anti-Neuroinflammatory Effect and Anti-Apoptotic Effect: Betaine Ameliorates Haloperidol-Induced Orofacial Dyskinesia in Rats

Bacillus Calmette–Guérin Vaccine Attenuates Haloperidol-Induced TD-like Behavioral and Neurochemical Alteration in Experimental Rats

(+)-9-Trifluoroethoxy-α-Dihydrotetrabenazine as a Highly Potent Vesicular Monoamine Transporter 2 Inhibitor for Tardive Dyskinesia

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