Lithium and valproate act on the GSK-3β signaling pathway to reverse manic-like behavior in an animal model of mania induced by ouabain

Valvassori, Samira S.; Dal‐Pont, Gustavo C.; Resende, Wilson R.; Jornada, Luciano K.; Peterle, Bruna R.; Machado, Alessandra Gonçalves; Farias, Hémelin Resende; Souza, Cláudio Teodoro de; Carvalho, André F.; Quevedo, Joao L De

doi:10.1016/j.neuropharm.2016.10.015

Cited by 38 publications

(15 citation statements)

References 88 publications

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“…Lithium inhibits GSK-3β and this effect has been suggested as one possible mechanism of action in BD patients (Stambolic et al, 1996 ; Li et al, 2010 ). Lithium and valproate also act on the GSK-3β signaling pathway to reverse the manic-like behavior in an animal model of mania induced by ouabain (Valvassori et al, 2016 ). Ouabain inhibits Na + /K + -ATPase activity, which induces hyperactivity.…”

Section: Models Of Bd and Clinical Translation To Drug Targetmentioning

confidence: 99%

Molecular Mechanisms of Bipolar Disorder: Progress Made and Future Challenges

Kim

Santos

Gage

et al. 2017

Front. Cell. Neurosci.

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Bipolar disorder (BD) is a chronic and progressive psychiatric illness characterized by mood oscillations, with episodes of mania and depression. The impact of BD on patients can be devastating, with up to 15% of patients committing suicide. This disorder is associated with psychiatric and medical comorbidities and patients with a high risk of drug abuse, metabolic and endocrine disorders and vascular disease. Current knowledge of the pathophysiology and molecular mechanisms causing BD is still modest. With no clear biological markers available, early diagnosis is a great challenge to clinicians without previous knowledge of the longitudinal progress of illness. Moreover, despite recommendations from evidence-based guidelines, polypharmacy is still common in clinical treatment of BD, reflecting the gap between research and clinical practice. A major challenge in BD is the development of effective drugs with low toxicity for the patients. In this review article, we focus on the progress made and future challenges we face in determining the pathophysiology and molecular pathways involved in BD, such as circadian and metabolic perturbations, mitochondrial and endoplasmic reticulum (ER) dysfunction, autophagy and glutamatergic neurotransmission; which may lead to the development of new drugs.

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Section: Models Of Bd and Clinical Translation To Drug Targetmentioning

confidence: 99%

Molecular Mechanisms of Bipolar Disorder: Progress Made and Future Challenges

Kim

Santos

Gage

et al. 2017

Front. Cell. Neurosci.

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“…MAPK is an important signal transduction pathway involved in neuronal survival. In this way, the mood stabilizers activate extracellular signal-regulated kinases (ERKs) and promote neurotrophic effects [55, 56, 57, 58]. In contrast, JNK is a proapoptotic molecule, and its inhibition has been suggested to cause neuroprotective and antioxidative effects [52, 59].…”

Section: Discussionmentioning

confidence: 99%

Effects of lithium and valproate on ERK/JNK signaling pathway in an animal model of mania induced by amphetamine

Valvassori¹,

Gava²,

Dal‐Pont³

et al. 2019

Heliyon

Self Cite

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Bipolar disorder (BD) is a severe and chronic psychiatric disorder, characterized by recurrent mood episodes of depression and mania. Some studies have indicated that there are ERK and JNK pathways alterations in the brain from bipolar patients. The animal model of mania induced by dextroamphetamine (d-AMPH) has been considered an excellent model to study intracellular alterations related to BD. The present study aimed to evaluate the effects of lithium (Li) and valproate (VPA) on the behavioral and ERK1/2/JNK1/2 signaling pathway in an animal model of mania induced by d-AMPH. Wistar rats were first given d-AMPH or saline (Sal) for 14 days, and then, between the 8th and 14th days, the rats were treated with Li, VPA, or Sal. The open-field test was used to evaluate the locomotion and exploration behaviors of rats. The levels of phosphorylated ERK1/2 and JNK1/2 were assessed in the hippocampus and frontal cortex of the rats. Li and VPA reversed the increased of locomotion and exploration induced by d-AMPH. The treatment with VPA or AMPH per se decreased the levels of pERK1 in the hippocampus. The treatment with VPA in the animals submitted to the administration of d-AMPH decreased the levels of ERK1, JNK-1, and JNK-2 phosphorylated in the hippocampus of the animals. The treatment with Li decreased the JNK-1 phosphorylated in the hippocampus of the animals submitted to the animal model of mania induced by d-AMPH. Although the association of VPA plus amphetamine alters some proteins involved in the JNK pathway in the hippocampus, these alterations were very random and seemed that were not related to the d-AMPH-induced manic-like behavior. These results suggest that the manic-like effects induced by d-AMPH and the antimanic effects of mood stabilizers, Li and VPA, are not related to the alteration on ERK1/2 and JNK1/2 pathways.

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“…Chronic lithium use has been reported to protect and attenuate TD in a population of patients with schizophrenia, whereas short‐term effects were disappointing . Discrepant results on GSK‐3β phosphorylation have been reported in the rat cortex following lithium exposure, with time‐ and region‐specific modulatory effects, making the antidyskinetic properties of lithium hard to predict, an altogether complex issue considering the wealth of neurotransmitters and signaling pathways it regulates . Several drug classes may produce upstream Akt activation to phosphorylate (inhibit) GSK‐3, such as sirolimus, glucagon‐like peptide‐1 analogues, rasagiline, green tea (epigallocatechin gallate), docosahexaenoic acid, meloxicam, AR‐A014418, and pridopidine.…”

Section: Gsk‐3β As a Key Signaling Molecule In Tdmentioning

confidence: 99%

Time for a New Slate in Tardive Dyskinesia Research

Blanchet

Lévesque

2020

Movement Disorders

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Despite high hopes and expectations that modern antipsychotic drug therapy would finally come to grips with tardive dyskinesia (TD) and pave the way for its burial, this potentially irreversible complication remained a fearsome and challenging issue, particularly in older age groups. Long-term prevalence rates >20% are still reported even in patients never exposed to firstgeneration drugs. 1-3 The gospel of TD has taught generations that striatal dopamine D 2 receptors become supersensitive during antipsychotic drug treatment. In the interval, the body of research supporting this hypothesis in human TD has remained deceptively thin, only to promote the development of novel antipsychotic drugs lacking robust affinity and selectivity for D 2 receptors supposed to avoid TD. Evidently, this has not panned out yet. Unfortunately, drug management of moderate-to-severe TD remains limited, attributable, in large part, to knowledge gaps in pathophysiology. Alleviation of TD scores afforded by vesicular monoamine transporter type 2 (VMAT2) blockade with tetrabenazine, deutetrabenazine, and valbenazine 4 proved their clinical relevance and supported two basic points in TD: (1) relative integrity of VMAT2 function and (2) implication of dopamine signaling. The proportion of responders' rate (≥50% reduction in baseline TD scores on the Abnormal Involuntary Movements Scale) <50% with these drugs 5 is a good indicator of the challenge awaiting clinicians managing TD. In this brief article, we present recent molecular findings indirectly suggesting the presence of enhanced striatal dopamine signaling in TD beyond D 2 receptors and wish to call out researchers and clinicians in considering new dopaminergic and nondopaminergic targets to improve management through modulation of glycogen synthase kinase (GSK)-3 activity.The mechanisms underlying delayed induction and maintenance of TD, as well as susceptibility of elderly subjects, remain elusive. The research community has relied essentially on experimental rodent models in order to achieve progress in the field. The short-acting dosing methods used for drug exposure in rodents have been questioned, given that they yield excessive peak and rapid trough levels in accordance with the short half-life of haloperidol in rodents (2-3 hours) relative to humans (>24 hours). 6 Furthermore, the relevance of the brief 3-week drug exposure proposed to assess the resulting vacuous chewing movements (VCM) response has also been raised, susceptible to reflect acute extrapyramidal reactions rather than genuine TD, leading some groups to advocate an extension of the haloperidol exposure to 6 months with more continuous forms of drug delivery with the drinking water or long-acting intramuscular depot preparations, before conducting further experiments. 7,8 Differences in phenomenology between early versus late VCM responses are also difficult to appreciate, but the acute impact of a shortacting haloperidol injection on VCM scores and distinct striatal dynorphin mRNA expression have argued for late ...

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Lithium and valproate act on the GSK-3β signaling pathway to reverse manic-like behavior in an animal model of mania induced by ouabain

Cited by 38 publications

References 88 publications

Molecular Mechanisms of Bipolar Disorder: Progress Made and Future Challenges

Molecular Mechanisms of Bipolar Disorder: Progress Made and Future Challenges

Effects of lithium and valproate on ERK/JNK signaling pathway in an animal model of mania induced by amphetamine

Time for a New Slate in Tardive Dyskinesia Research

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