Microscopy images showing dendrites, the rod-like branches of brain cells, with tiny protrusions called dendritic spines that are critical for memory and learning. Normal mice show similar spine density with (bottom left) and without KD025 treatment (top left). In mice carrying schizophrenia-associated gene variants, the tiny protrusions are visibly reduced without treatment (top right) but restored after KD025 treatment (bottom right). Scale bar: 5 μm.
Image Credit: Tanaka et al., 2026
Scientific Frontline: Extended "At a Glance" Summary: Selective ROCK2 Inhibition in Schizophrenia
The Core Concept: Selective inhibition of Rho kinase 2 (ROCK2) via the drug KD025 is a novel therapeutic approach aimed at improving cognitive impairments and behavioral abnormalities in schizophrenia.
Key Distinction/Mechanism: Unlike current antipsychotic medications that primarily target positive symptoms but often cause severe metabolic and motor adverse effects, KD025 selectively inhibits ROCK2 to restore dendritic spine density in the prefrontal cortex without inducing hypotension or extrapyramidal symptoms.
Major Frameworks/Components:
- ARHGAP10 Gene Variant: A genetic mutation identified in patients that alters the activity of Rho-kinase (ROCK) signaling and neuronal stability.
- ROCK2 (Rho kinase 2): A specific kinase subtype heavily expressed in the brain that regulates brain cell function and neural connectivity.
- KD025: A ROCK2-selective inhibitor utilized to alleviate deficits in working memory, thinking, and visual discrimination.
- Dendritic Spine Density: The structural connectivity of neurons in the prefrontal cortex, which is often degraded in schizophrenia and shown to be restored via selective ROCK2 inhibition.
Branch of Science: Neuropsychopharmacology, Psychiatry, Molecular Biology.
Future Application: The development of next-generation, safer antipsychotic therapies that directly address cognitive dysfunction—a major unmet clinical need in the long-term psychiatric care of patients with schizophrenia.
Why It Matters: Addressing the severe cognitive deficits that affect over 80% of schizophrenia patients without triggering the cardiovascular, hormonal, or metabolic side effects of traditional antipsychotics presents a major breakthrough in improving patient outcomes and overall quality of life.
By Targeting a Schizophrenia-Associated Brain Protein, KD025 Restored Neural Connections and Reduced Schizophrenia Symptoms in Mice with Fewer Side Effects
Schizophrenia is a serious brain disorder that causes confused thinking, severe memory problems, and hallucinations. It affects about 23 million people worldwide, with cognitive dysfunction present in over 80% of patients. A research group led by scientists from Nagoya University in Japan tested a drug used to treat an immune disease to see if it could reduce schizophrenia-related symptoms in mice. The findings, published in Molecular Psychiatry, show that KD025 restored connections between neurons and significantly improved memory and visual recognition in mice, without causing the serious side effects common to current schizophrenia medications.
Need for Safer Treatments for Schizophrenia
Current medications help with some symptoms, but they often do not improve cognitive function. They also cause serious side effects such as hormonal disruptions, involuntary muscle movements, and weight gain, leading many patients to discontinue treatment. Therefore, better options are urgently needed.
Researchers focused on a gene called ARHGAP10. Variants of this gene (small changes in the DNA sequence) are much more common in people with schizophrenia than in the general population.
“ARHGAP10 controls the activity of a brain protein called ROCK2. In mice with these genetic variants, ROCK2 becomes overactive. In a previous study, we found that this overactivity appears to damage connections between neurons and impair cognition,” said Rinako Tanaka, co-lead author and former project assistant professor at Nagoya University’s Graduate School of Medicine.
Repurposing Drugs to Achieve Better Treatment
The team tested KD025, approved in the United States to treat an immune disease called chronic graft-versus-host disease, which can occur after bone marrow transplants. In mice engineered to carry schizophrenia-associated gene variants, the drug decreased the overactivity of ROCK2.
Furthermore, KD025 restored the density of tiny structures on neurons called dendritic spines, which are critical for memory. These had been reduced in mice carrying schizophrenia-associated gene variants. The drug had no effect on healthy mice.
“Importantly, KD025 did not cause the side effects typical of current antipsychotic drugs. At effective doses, it caused no involuntary movements, hormonal abnormalities, or significant changes in blood pressure or blood sugar. This safety profile sets it apart from older antipsychotics like haloperidol and newer drugs like clozapine,” said Hiroyuki Mizoguchi, coauthor and associate professor from the Department of Neuropsychopharmacology and Hospital Pharmacy at Nagoya University.
Because KD025 has already been through clinical safety trials for another condition, human trials for schizophrenia could start sooner than for a new drug. While the researchers caution that all experiments were conducted in mice and that human studies are needed, the findings point to a promising target for treatments that are more effective and better tolerated by patients.
Future studies will investigate how KD025 improves brain cell connections and function and will further evaluate its safety and efficacy to support human trials.
Reference material: What Is: Schizophrenia
Funding: This study was supported by the Japan Agency for Medical Research and Development (AMED) (grant numbers: JP21wm0425007, JP21wm0425017, JP25wm0625518, JP23ak0101215, JP24ak0101221, JP22gm1410011, JP24zf0127011, and JP23gm1910005); the Japan Society for the Promotion of Science (JSPS) KAKENHI (grant numbers: JP23H02669, JP23K19425, and JP24K18365); the Japanese SRF Grant for Biomedical Research; the Takeda Science Foundation; and the Toyoaki Scholarship Foundation.
Published in journal: Molecular Psychiatry
Authors: Rinako Tanaka, Jingzhu Liao, Yue Liu, Wenjun Zhu, Kisa Fukuzawa, Masamichi Kondo, Masahito Sawahata, Daisuke Mori, Akihiro Mouri, Hisayoshi Kubota, Daiki Tachibana, Yohei Kobayashi, Tetsuo Matsuzaki, Taku Nagai, Toshitaka Nabeshima, Kozo Kaibuchi, Norio Ozaki, Hiroyuki Mizoguchi, and Kiyofumi Yamada
Source/Credit: Nagoya University
Reference Number: phar051326_01