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Antipsychotic drugs counteract autophagy and mitophagy in multiple sclerosis.

ABSTRACT: Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease characterized by myelin damage followed by axonal and ultimately neuronal loss. The etiology and physiopathology of MS are still elusive, and no fully effective therapy is yet available. We investigated the role in MS of autophagy (physiologically, a controlled intracellular pathway regulating the degradation of cellular components) and of mitophagy (a specific form of autophagy that removes dysfunctional mitochondria). We found that the levels of autophagy and mitophagy markers are significantly increased in the biofluids of MS patients during the active phase of the disease, indicating activation of these processes. In keeping with this idea, in vitro and in vivo MS models (induced by proinflammatory cytokines, lysolecithin, and cuprizone) are associated with strongly impaired mitochondrial activity, inducing a lactic acid metabolism and prompting an increase in the autophagic flux and in mitophagy. Multiple structurally and mechanistically unrelated inhibitors of autophagy improved myelin production and normalized axonal myelination, and two such inhibitors, the widely used antipsychotic drugs haloperidol and clozapine, also significantly improved cuprizone-induced motor impairment. These data suggest that autophagy has a causal role in MS; its inhibition strongly attenuates behavioral signs in an experimental model of the disease. Therefore, haloperidol and clozapine may represent additional therapeutic tools against MS.

SUBMITTER: Patergnani S

PROVIDER: S-EPMC8214668 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The beliefs that antipsychotic drugs (APDs) are 1) effective only to treat delusions and hallucinations (positive symptoms), 2) that typical and atypical APDs differ only in ability to cause extrapyramidal side effects, and 3) that their efficacy as antipsychotics is due solely to their dopamine D2 receptor blockade are outmoded concepts that prevent clinicians from achieving optimal clinical results when prescribing an APD. Atypical APDs are often more effective than typical APDs in treating negative symptoms, cognitive impairment, and mood symptoms as well as reducing the risk for suicide and decreasing aggression. This applies not only to those diagnosed with schizophrenia or schizoaffective disorder but also to bipolar disorder, major depression, and other psychiatric diagnoses. The greater advantage of an atypical APD is not evident in all patients for every atypical APD due, in part, to individual differences in genetic and epigenetic endowment and differences in the pharmacology of the atypical APDs, their mode of action being far more complex than that of the typical APDs. A common misconception is that among the atypical APDs, only clozapine is effective for reducing psychosis in treatment-resistant schizophrenia. Aripiprazole, lurasidone, olanzapine, and risperidone also can be more effective than typical APDs for treatment-resistant schizophrenia; clozapine is uniquely indicated for reducing the risk for suicide. The ability of the atypical APDs to improve cognition and negative symptoms in some patients together with lower propensity to cause tardive dyskinesia (an underappreciated advantage) leads to better overall outcomes. These advantages of the atypical APDs in efficacy and safety are due, in part, to initiation of synaptic plasticity via direct and indirect effects of the atypical APDs on a variety of proteins, especially G proteins, and release of neurotrophins (e.g., brain-derived neurotrophic factor). The typical APDs beneficial effects on psychosis are mainly the result of D2 receptor blockade, which can be associated with serious side effects and lack of tolerability.

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Antipsychotic drugs counteract autophagy and mitophagy in multiple sclerosis.

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