The Janus face of antipsychotics in glial cells: Focus on glioprotection

Abstract

Antipsychotics are commonly prescribed to treat several neuropsychiatric disorders, including schizophrenia, mania in bipolar disorder, autism spectrum disorder, delirium, and organic or secondary psychosis, for example, in dementias such as Alzheimer's disease. There is evidence that typical antipsychotics such as haloperidol are more effective in reducing positive symptoms than negative symptoms and/or cognitive deficits. In contrast, atypical antipsychotic agents have gained popularity over typical antipsychotics, due to fewer extrapyramidal side effects and their theoretical efficacy in controlling both positive and negative symptoms. Although these therapies focus on neuron-based therapeutic schemes, glial cells have been recognized as important regulators of the pathophysiology of neuropsychiatric disorders, as well as targets to improve the efficacy of these drugs. Glial cells (astrocytes, oligodendrocytes, and microglia) are critical for the central nervous system in both physiological and pathological conditions. Astrocytes are the most abundant glial cells and play important roles in brain homeostasis, regulating neurotransmitter systems and gliotransmission, since they express a wide variety of functional receptors for different neurotransmitters. In addition, converging lines of evidence indicate that psychiatric disorders are commonly associated with the triad neuroinflammation, oxidative stress, and excitotoxicity, and that glial cells may contribute to the gliotoxicity process. Conversely, glioprotective molecules attenuate glial damage by generating specific responses that can protect glial cells themselves and/or neurons, resulting in improved central nervous system (CNS) functioning. In this regard, resveratrol is well-recognized as a glioprotective molecule, including in clinical studies of schizophrenia and autism. This review will provide a summary of the dual role of antipsychotics on neurochemical parameters associated with glial functions and will highlight the potential activity of glioprotective molecules to improve the action of antipsychotics.

Keywords: Antipsychotics; glial cells; glioprotection; resveratrol; schizophrenia.

Figure 1.

The tripartite synapse as a target of antipsychotics. Presynaptic neurons release neurotransmitters (dopamine, serotonin, glutamate), accordingly to their specialization and brain region, from synaptic vesicles within the synaptic cleft. Neurotransmitters interact with their specific ionotropic and/or metabotropic receptors at postsynaptic neurons. Astrocytes also express dopamine and serotonin receptors, as well as glutamate transporters, therefore modulating synaptic transmission. Typical and atypical antipsychotics, TA and AA, respectively, can act blocking mainly neuronal dopamine and/or serotonin receptors. In addition, AA can modulate glutamate receptors and transporters (dashed lines). Therefore, astrocytes can also be putative targets of antipsychotic medications, as discussed in the text. Astrocytes actively participate in NFκB-coordinated inflammatory, mitochondrial responses, and glutamate metabolism via GS activity and GSH synthesis, all of which are involved in the pathogenesis of neuropsychiatric disorders and may be also modulated by antipsychotics. Finally, there is a close relationship between astrocytes and microglia, particularly related to inflammatory response.

Figure 2.

The Janus face of antipsychotics. Glial cells display key roles in the pathogenesis and progression of neuropsychiatric disorders. Accumulating evidence has shown that antipsychotics can affect glial functions. The long-term use of these medications, in association with age, may lead to changes in inflammatory response, oxidative stress, and glutamate homeostasis imbalance/excitotoxicity. Of note, all these processes are also closely related to neuropsychiatric disorders. Therefore, glioprotection (glial-based preventive/therapeutic strategies) might emerge to avoid such detrimental effects.