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REVIEW article

Front. Drug Deliv.
Sec. CNS Drug Delivery
Volume 4 - 2024 | doi: 10.3389/fddev.2024.1364037
This article is part of the Research Topic Innovative Approaches to Overcome Treatment-Resistant Central Nervous System Disorders View all articles

A Selective Review of Inhibitors of Protein Kinase C Gamma: A Neuroplasticity-Related Common Pathway for Psychiatric Illness

Provisionally accepted
Marco Grados Marco Grados 1,2*Mona Salehi Mona Salehi 3Aida Lotfi Aida Lotfi 4Sagar Dua Sagar Dua 5Isabella Xie Isabella Xie 6
  • 1 Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD, United States
  • 2 Johns Hopkins University, Baltimore, Maryland, United States
  • 3 School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States
  • 4 Qazvin University of Medical Sciences, Qazvin, Qazvin, Iran
  • 5 All India Institute of Medical Sciences, New Delhi, National Capital Territory of Delhi, India
  • 6 Palo Alto University, Palo Alto, California, United States

The final, formatted version of the article will be published soon.

    Psychotropics are currently developed and marketed with a limited understanding of their mechanism of action. The notion that protein kinase C (PKC) activity is highly relevant to learning and memory function stems from experiments in the 1980s, which associated protein kinase alpha (pka) and pkc to animal models of associative learning, opening an area of exploration for psychotropic development. The PKC family consists of several isoforms, including PKC alpha, beta1, beta1, gamma, delta and epsilon among others. In particular, PKC gamma (PRKCG) is highly brain-expressed and is singled out as a candidate for modulation in psychiatric illness. With hundreds of identified substrates, PRKCG affects multiple pathways relevant for regulation of neuronal health. In this review, converging lines of evidence are presented in the context of psychotropic drug action, which point to downregulation of PKC activity as a potential common mechanism across several psychiatric disorders. Using this mechanism through more targeted psychotropic action may then be used to develop agents that further ameliorate psychiatric symptom expression. Psychotropics including fluoxetine, tricyclics, lithium, valproate, ketamine and others are explored in relation to their effect of PKC, finding that across all drugs examined, a downregulation with chronic-but not acute-use constitutes their putative effect in ameliorating symptoms. This effect is compounded by findings that suggest that PKCs, and PRKCG in particular, promote neuroplastic effects by their downregulation. This effect is in contrast to PKC activators, which have been used in neurodegenerative disorders such as Alzheimer’s disease. Cross-disorder mechanisms need to continue to be explored in neuropsychiatric illness and targeted treatments developed in turn to address treatment-resistant conditions.

    Keywords: PKC - protein kinase C, Anxiety, neuroplasticity, Fluoxetine (CID: 62857), PKC gamma

    Received: 01 Jan 2024; Accepted: 24 Jul 2024.

    Copyright: © 2024 Grados, Salehi, Lotfi, Dua and Xie. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Marco Grados, Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, 21287, MD, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.