NLRP3/Caspase-1-Mediated Pyroptosis of Astrocytes Induced by Antipsychotics Is Inhibited by a Histamine H1 Receptor-Selective Agonist

Abstract

Emerging data indicate that antipsychotic treatment causes brain volume loss and astrocyte death, but the mechanisms remain elusive. Pyroptosis, inflammatory cell death characterized by the formation of inflammatory bodies, increased expression of nod-like receptor proteins (NLRPs) such as NLRP3, and activation of caspases and gasdermin D (GSDMD) are largely associated with innate immunity, inflammation, and cell injury/death. However, the main effect of antipsychotics on astrocyte pyroptotic signaling and the molecular mechanisms remain obscure. In the present study, 72-h treatment with olanzapine, quetiapine, risperidone, or haloperidol significantly decreased the viability of astrocytes. Twenty-four hour treatment with olanzapine, quetiapine, risperidone, or haloperidol dose-dependently increased the protein expression of astrocytic NLRP3, NLRP6, caspase-1, caspase-4, and GSDMD. Co-treatment with a histamine H1 receptor agonist, 2-(3-trifluoromethylphenyl) histamine (FMPH), dose-dependently reduced the increased expression of NLRP3, caspase-1 and GSDMD induced by olanzapine, quetiapine, risperidone, or haloperidol. Moreover, olanzapine, quetiapine, risperidone, or haloperidol treatment induced pore formation in the membranes of astrocytes, and these effects were inhibited by FMPH co-treatment. Taken together, antipsychotic treatment activated astrocyte pyroptotic signaling, and these effects may be related to antipsychotic-induced astrocyte death. H1 receptor activation is an effective treatment strategy to suppress antipsychotic-induced astrocyte pyroptosis and inflammation.

Astrocytic Abnormalities in Schizophrenia

“…These components are strongly linked to innate immunity, hyperinflammation, and cell damage/expiry. The same study found the main effect of antipsychotic treatments on astrocyte pyroptotic pathways and the molecular processes that could be exerted through inflammasome pathways [89]. In this experiment, 72-h therapy with olanzapine, quetiapine, risperidone, or haloperidol strongly attenuated the astrocytes' viability.…”

“…In addition, SCZ patients are often treated with antipsychotic medications that cause brain volume reduction and astrocyte expiry in a process called pyroptosis or proinflammatory cellular expiry [89]. This process involves the formation of inflammatory bodies and enhanced production of complexes such as NLRP3, parallel with the induction of caspases and gasdermin D (GSDMD).…”

“…24-h therapy by olanzapine, quetiapine, risperidone, or haloperidol dose dependently augmented the protein synthesis of astrocytic NLRP3, NLRP6, caspase-1, caspase-4, and GSDMD. Co-administration with a histamine H1 receptor agonist, 2-(3-trifluoromethylphenyl) histamine (FMPH), attenuated the raised synthesis of NLRP3, caspase-1, and GSDMD activated via olanzapine, quetiapine, risperidone, or haloperidol [89]. Moreover, olanzapine, quetiapine, risperidone, or haloperidol treatment-induced pore formation in the astrocyte membranes was suppressed via FMPH co-treatment [89].…”

“…When taken together, astrocytic inflammasomes and hyperinflammation are implicated in SCZ, and activation of astrocyte pyroptotic pathways could be due to antipsychotic-activated astrocyte expiry. Further, H1 receptor activation could be a robust therapeutic approach to inhibit antipsychotic-activated astrocyte pyroptosis and hyperinflammation [90]. However, more studies should assess astrocyte-specific (or other CNS cell-specific) inflammasomes and consider the noncanonical pathways to understand more fully how these innate complexes contribute to hyperinflammatory cytokine secretion and neuronal/glial damage.…”

The role of hypothalamic endoplasmic reticulum stress in schizophrenia and antipsychotic-induced weight gain: A narrative review

“…The role of other antipsychotics on hypothalamic inflammation has not been elucidated fully. In astrocytes, olanzapine, risperidone, quetiapine, and haloperidol increase IL-1β (He et al, 2022a). In microglia, as has been reviewed, haloperidol and risperidone reduce IL-1β induced by poly (I:C) treatment, but increase IL-6 and TNF-α (Giridharan et al, 2020).…”