Neuropharmacological Potential of Rho-Kinase Inhibition in Schizophrenia-Associated Mutations

Schizophrenia, a complex psychiatric disorder, is widely recognized to have a genetic component, with copy-number variations playing a significant role. Specifically, alterations in the copy number of the ARHGAP10 gene have been associated with schizophrenia symptoms. In a groundbreaking study published in Pharmacological Research, a team of researchers from Nagoya University in Japan investigated the potential therapeutic effects of inhibiting Rho-kinase (ROCK) in a mouse model carrying mutations in the ARHGAP10 gene. Their findings shed light on the amelioration of decreased spine density in the medial prefrontal cortex and methamphetamine-induced cognitive dysfunction, presenting novel possibilities for treating schizophrenia patients.

The Role of ARHGAP10 and Rho-kinase Signaling

ARHGAP10 encodes a protein that regulates the Rho GTPase family, a group of enzymes crucial for cellular processes. Perturbations in the RhoA member of this family have been linked to schizophrenia. Building on this knowledge, the researchers hypothesized that targeting downstream factors of RhoA, particularly ROCK, could hold promise as a therapeutic strategy. Activation of the RhoA/ROCK signaling pathway has been implicated in various risk factors associated with schizophrenia.

Model Mice Mimicking Schizophrenia Phenotypes

By breeding model mice with mutations in their ARHGAP10 gene, the researchers successfully replicated key symptoms observed in human schizophrenia patients. These mice exhibited altered spine density, cognitive dysfunction induced by methamphetamine, and activation of the RhoA/ROCK signaling pathway. Notably, cognitive impairment in schizophrenia has been linked to alterations in spine morphology.

Unraveling the Impact of Rho-Kinase Inhibition

Led by lead researcher Rinako Tanaka from Nagoya University Graduate School of Medicine, the team collaborated with Fujita Health University to explore the therapeutic potential of fasudil, a drug known for its ROCK-inhibiting properties. The objective was to restore pyramidal neuron density in the medial prefrontal cortex, a brain region critical for attention and long-term memory. Additionally, they aimed to alleviate methamphetamine-induced cognitive impairment in the model mice.

Promising Results: Ameliorating Symptoms

Through the administration of fasudil, the researchers successfully inhibited ROCK in the model mice carrying ARHGAP10 mutations. The treatment resulted in the restoration of pyramidal neuron density in the medial prefrontal cortex, suggesting a potential reversal of structural abnormalities associated with schizophrenia. Moreover, the mice treated with fasudil demonstrated improved performance on visual discrimination tests, indicating a positive impact on cognitive function compromised by methamphetamine.

Implications for Schizophrenia Treatment

Lead researcher Rinako Tanaka emphasized the significance of their findings, shedding light on the underlying mechanisms through which ROCK contributes to neuropathological changes in spine morphology and cognitive vulnerability induced by methamphetamine in mice carrying ARHGAP10 mutations. By targeting Rho-kinase signaling, new therapeutic approaches could emerge for the treatment of schizophrenia, particularly in patients with ARHGAP10 gene mutations. Rho kinase inhibitors like fasudil or downstream modulators may hold promise as future therapeutic drugs for this debilitating disorder.

The identification of ROCK as a potential therapeutic target in schizophrenia provides a deeper understanding of the molecular mechanisms underlying the disorder. By inhibiting ROCK, researchers were able to reverse the decreased spine density observed in the medial prefrontal cortex. This finding is significant, as the medial prefrontal cortex plays a crucial role in executive functions, attention, and memory processes, which are often impaired in individuals with schizophrenia.

Furthermore, the improvement in cognitive function observed in mice treated with fasudil is particularly noteworthy. Methamphetamine-induced cognitive dysfunction is a common feature in individuals with schizophrenia, and finding a means to alleviate this impairment represents a major breakthrough. The ability of fasudil to mitigate cognitive deficits suggests that ROCK inhibition may hold promise for restoring cognitive function in schizophrenia patients.

A Step in the Right Direction

The observed restoration of spine density and cognitive improvement in mice treated with fasudil opens up new avenues for the development of innovative treatment strategies. This research provides valuable insights into the underlying pathophysiology of schizophrenia and holds the promise of translating into novel therapeutic interventions for patients suffering from this complex disorder that has long eluded effective treatment options.

The use of fasudil in this study highlights the importance of repurposing existing drugs for new indications. Fasudil is an FDA-approved drug primarily used for the treatment of cerebral vasospasm following subarachnoid hemorrhage. By exploring its effects on ROCK inhibition in the context of schizophrenia, researchers have identified a potential alternative use for this medication. Repurposing drugs offers several advantages, including reduced costs and accelerated development timelines, which could expedite the translation of this research into clinical applications.

It is important to note that while this study provides valuable insights into the potential therapeutic effects of ROCK inhibition, further research is needed to fully understand the clinical implications. The study was conducted on a mouse model, and extrapolating these findings to human patients requires careful consideration. However, the results of this study pave the way for future investigations into ROCK inhibitors as a viable treatment option for schizophrenia.

Study DOI: 10.1016/j.phrs.2022.106589

Engr. Dex Marco Tiu Guibelondo, BS Pharm, RPh, BS CpE

Editor-in-Chief, PharmaFEATURES