Therapeutic potential for KCC2-targeted neurological diseases

Kazuo Tomita; Yoshikazu Kuwahara; Kento Igarashi; Junichi Kitanaka; Nobue Kitanaka; Yuko Takashi; Koh-Ichi Tanaka; Mehryar Habibi Roudkenar; Amaneh Mohammadi Roushandeh; Akihiro Kurimasa; Yoshihiro Nishitani; Tomoaki Sato

doi:10.1016/j.jdsr.2023.11.001

Therapeutic potential for KCC2-targeted neurological diseases

Jpn Dent Sci Rev. 2023 Dec:59:431-438. doi: 10.1016/j.jdsr.2023.11.001. Epub 2023 Nov 11.

Authors

Kazuo Tomita^{1

2}, Yoshikazu Kuwahara^{1

3}, Kento Igarashi^{1

2}, Junichi Kitanaka⁴, Nobue Kitanaka^{4

5}, Yuko Takashi⁶, Koh-Ichi Tanaka^{1

2}, Mehryar Habibi Roudkenar^{1

7}, Amaneh Mohammadi Roushandeh⁸, Akihiro Kurimasa³, Yoshihiro Nishitani⁶, Tomoaki Sato¹

Affiliations

¹ Department of Applied Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan.
² Division of Pharmacology, Department of Pharmacy, School of Pharmacy, Hyogo Medical University, Hyogo 650-8530, Japan.
³ Division of Radiation Biology and Medicine, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Miyagi, 983-8536, Japan.
⁴ Laboratory of Drug Addiction and Experimental Therapeutics, Schoolof Pharmacy, Hyogo Medical University, Hyogo 650-8530, Japan.
⁵ Department of Pharmacology, School of Medicine, Hyogo Medical University, Hyogo 663-8501, Japan.
⁶ Department of Restorative Dentistry and Endodontology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan.
⁷ Burn and Regenerative Medicine Research Center, Velayat Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht 41937-13194, Iran.
⁸ Department of Anatomy, School of Biomedical Sciences, Medicine & Health, UNSW Sydney, Sydney, NSW 2052, Australia.

Abstract

Patients with neurological diseases, such as schizophrenia, tend to show low K⁺-Cl^- co-transporter 2 (KCC2) levels in the brain. The cause of these diseases has been associated with stress and neuroinflammation. However, since the pathogenesis of these diseases is not yet fully investigated, drug therapy is still limited to symptomatic therapy. Targeting KCC2, which is mainly expressed in the brain, seems to be an appropriate approach in the treatment of these diseases. In this review, we aimed to discuss about stress and inflammation, KCC2 and Gamma-aminobutyric acid (GABA) function, diseases which decrease the KCC2 levels in the brain, factors that regulate KCC2 activity, and the possibility to overcome neuronal dysfunction targeting KCC2. We also aimed to discuss the relationships between neurological diseases and LPS caused by Porphyromonas gingivalis (P. g), which is a type of oral bacterium. Clinical trials on oxytocin, sirtuin 1 (SIRT1) activator, and transient receptor potential cation channel subfamily V Member 1 activator have been conducted to develop effective treatment methods. We believe that KCC2 modulators that regulate mitochondria, such as oxytocin, glycogen synthase kinase 3β (GSK3β), and SIRT1, can be potential targets for neurological diseases.

Keywords: GABA; Inflammation; KCC2; Neurological diseases; Therapeutic target.

Publication types

Review