The mammalian target of rapamycin (mTOR) kinase mediates haloperidol-induced cataleptic behavior

Ramírez-Jarquín, Uri Nimrod; Shahani, Neelam; Pryor, William M.; Usiello, Alessandro; Subramaniam, Srinivasa

doi:10.1038/s41398-020-01014-x

Cited by 15 publications

(23 citation statements)

References 62 publications

(60 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results are in line with observations from the real-time metabolic assays, although all antipsychotics lowered the expression of iNOS, indicating a different mechanism for metabolic reprogramming between the tested antipsychotics. Recent studies have shown that haloperidol has capabilities in increasing mTORC1 activity in neurons, which was also linked to extrapyramidal motor side effects [57][58][59]. Increased mTORC1 activity and glycolysis was also seen in olanzapine [60], a second-generation antipsychotic, similar to what we found in cells treated with risperidone.…”

Section: Discussionsupporting

confidence: 86%

Effects of Haloperidol, Risperidone, and Aripiprazole on the Immunometabolic Properties of BV-2 Microglial Cells

Rački

Marcelić

Štimac

et al. 2021

IJMS

View full text Add to dashboard Cite

Microglial cells are resident macrophages in the brain that have been implicated in the pathophysiology of schizophrenia. There is a lack of studies covering the effects of antipsychotics on microglial cells. The current literature points to a possible anti-inflammatory action without clear mechanisms of action. The aim of this study is to characterize the effects of haloperidol, risperidone and aripiprazole on BV-2 microglial cells in in vitro conditions. We have used immunofluorescence and flow cytometry to analyze the classical pro and anti-inflammatory markers, while a real-time metabolic assay (Seahorse) was used to assess metabolic function. We analyzed the expression of p70S6K to evaluate the mTOR pathway activity with Western blot. In this study, we demonstrate the varying effects of haloperidol, risperidone and aripiprazole administration in BV-2 microglial cells. All three tested antipsychotics were successful in reducing the pro-inflammatory action of microglial cells, although only aripiprazole increased the expression of anti-inflammatory markers. Most significant differences in the possible mechanisms of action were seen in the real-time metabolic assays and in the mTORC1 signaling pathway activity, with aripiprazole being the only antipsychotic to reduce the mTORC1 activity. Our results shed some new light on the effects of haloperidol, risperidone and aripiprazole action in microglial cells, and reveal a novel possible mechanism of action for aripiprazole.

show abstract

Section: Discussionsupporting

confidence: 86%

Effects of Haloperidol, Risperidone, and Aripiprazole on the Immunometabolic Properties of BV-2 Microglial Cells

Rački

Marcelić

Štimac

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…Thus, in the catalepsy test, metformin significantly reduced the latency of descent from the bar in all tests performed, regardless of the time. These results are in agreement to those previously presented by Adedeji et al [33], that metformin reduces the period of immobilization and improves the ability of behavioral adaptation [34].…”

Section: Discussionsupporting

confidence: 94%

Beneficial effects of metformin on haloperidol-induced motor deficits in rats. A behavioral assessment

Jîtcă

Gáll

Vari

et al. 2021

Acta Marisiensis - Seria Medica

View full text Add to dashboard Cite

Objective: One of the most common side effects of haloperidol is the extrapyramidal syndrome, resulting from inhibition of nigrostriatal dopaminergic circuits and mitochondrial dysfunction due to structural similarities to pyridinium derivative, MPP+ that induce oxidative stress. In exchange, the use of metformin appears to enhance neurogenesis, energy metabolism, and oxidative status, so these properties can be speculated in the context of drug-induced pseudoparkinsonism by haloperidol. Methods: To assess motor coordination and activity, rodents were divided into four groups: CTR (n = 10) - animals that received distilled water, METF (n = 10) - animals that received metformin 500 mg / kgbw, HAL (n = 10) - animals that received haloperidol 2mg / kgbw, HALMETF (n = 10) - haloperidol 2mg / kgbw and metformin 500 mg / kgbw. The treatment was administered for 34 days at the same time by gastric gavage, during which time behavioral tests, rotarod (days 7, 14, 21, 28), catalepsy (day 30), open field (day 32) and novel object recognition (day 34) were performed. Results: The monitored parameters, showed significant differences between the groups of interest (HAL and HALMETF respectively), so that the administration of metformin at the beginning of treatment reduces the cataleptic behavior. The HALMETF group shows an attenuation of the motor deficit during the rotarod test and the freezing period from the Open Field test, is diminished. Conclusions: Metformin treatment has a beneficial effect in haloperidol-treated rats, demonstrated by decreased cataleptic behavior, improved motor performance and reduced haloperidol-induced anxiety behavior.

show abstract

“…Western blotting from striatal tissue were carried as described before [78, 79] . Striatal tissue was rinsed briefly in PBS and directly lysed in lysis buffer [50 mM Tris-HCl (pH 7.4), 150 mM NaCl, 1% Triton X-100, 1x protease inhibitor cocktail (Roche, Sigma) and 1x phosphatase inhibitor (PhosStop, Roche, Sigma)], sonicated for 2 x 5 sec at 20% amplitude, and cleared by centrifugation for 10 min at 11,000 g at 4°C.…”

Section: Methodsmentioning

confidence: 99%

Rhes Deletion Prevents Age-Dependent Selective Motor Deficits and Reduces Phosphorylation of S6K in Huntington Disease Hdh150Q(CAG) Knock-In Mice

Subramaniam

Hernández

Swarnkar

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Huntington disease (HD) is a neurodegenerative disease caused by a CAG trinucleotide repeat expansion in the huntingtin (mHTT) protein. This expansion is thought to promote striatal atrophy by a combination of cell- and non-cell-autonomous processes, but the mechanisms are unclear. Previous evidence suggests that the striatal-enriched SUMO E3-like protein Rhes could play a pathological role in HD. Rhes interacts with, and SUMOylates, mHTT and promotes toxicity and Rhes deletion ameliorates the HD phenotype in cell and severe mouse models of HD. However, the effect of Rhes on less severe knock-in models of HD remains obscure. Here, we report that a Hdh(CAG)150 knock-in murine model of HD showed diminished body weight but no changes in locomotor coordination or activity at 80 and 100 weeks of age. Conversely, Rhes deletion did not impact the body weight or behaviors but caused a significant reduction of gait, clasping, and tremor behaviors in Hdh150Q/150Q mice. Rhes deletion did not affect the loss of striatal DARPP-32 protein levels but abrogated the hyper ribosomal protein S6 kinase beta-1 (S6K) phosphorylation, which is a substrate for a mechanistic target of rapamycin complex 1 (mTORC1) signaling, in Hdh(CAG)150 mice. Interestingly, striatal Rhes protein levels were downregulated in the striatum of Hdh(CAG)150 mice, indicating a potential compensatory mechanisms at work. Thus, Rhes deletion prevents age-dependent behavioral deficits and diminishes hyperactive mTORC1-S6K signaling in Hdh(CAG)150 knock-in mice HD striatum.

show abstract

The mammalian target of rapamycin (mTOR) kinase mediates haloperidol-induced cataleptic behavior

Cited by 15 publications

References 62 publications

Effects of Haloperidol, Risperidone, and Aripiprazole on the Immunometabolic Properties of BV-2 Microglial Cells

Effects of Haloperidol, Risperidone, and Aripiprazole on the Immunometabolic Properties of BV-2 Microglial Cells

Beneficial effects of metformin on haloperidol-induced motor deficits in rats. A behavioral assessment

Rhes Deletion Prevents Age-Dependent Selective Motor Deficits and Reduces Phosphorylation of S6K in Huntington Disease Hdh150Q(CAG) Knock-In Mice

Contact Info

Product

Resources

About