Peptide Formulation Promising for Schizophrenia Cognitive Decline

Schizophrenia is a severe mental disorder characterized by a variety of symptoms including hallucinations, impaired cognitive abilities, and disorganized speech or behavior. This condition is linked to anomalies in neurotransmission due to an imbalance of chemical neurotransmitters. Current treatments typically involve antipsychotic drugs, which are not without significant drawbacks. These include adverse effects and a heightened risk of cardiovascular disease. Additionally, the efficacy of these drugs is often limited due to the selective permeability of the blood-brain barrier (BBB), which regulates the movement of molecules into the brain.

Overcoming the challenge posed by the BBB to deliver effective treatments for schizophrenia has been a primary focus for researchers. A promising approach is receptor-mediated transcytosis (RMT) using low-density lipoprotein receptor-related protein 1 (LRP1). Associate Professor Eijiro Miyako from the Japan Advanced Institute of Science and Technology (JAIST) led a research team to explore this method, in collaboration with Prof. Yukio Ago from Hiroshima University, Prof. Shinsaku Nakagawa from Osaka University, Prof. Takatsugu Hirokawa from Tsukuba University, and Dr. Kotaro Sakamoto of Ichimaru Pharcos Co., Ltd. Their findings were published in the JACS Au journal on June 20, 2024.

The researchers were motivated by earlier studies that showed the role of vasoactive intestinal peptide receptor 2 (VIPR2) gene duplication in schizophrenia. They had also discovered a novel peptide named KS-133, which acts as a selective antagonist to VIPR2, leading to its downregulation. However, KS-133 faced a significant limitation due to its poor permeability across the BBB.

To address this issue, the team designed a brain-targeting peptide, KS-487, which can bind specifically to LRP1 and facilitate RMT. They then developed a nanoparticle-based drug delivery system (DDS) where KS-133 was encapsulated with KS-487. This system was tested for its effectiveness in treating schizophrenia.

The administration of these peptide formulations via the DDS enabled the effective distribution of the drug in the brains of mice. Pharmacokinetic analysis confirmed that the brain-targeting peptide played a crucial role in delivering KS-133 into brain tissue. The efficacy of the DDS was further evaluated in mice with induced schizophrenia, characterized by elevated activation of VIPR2. Mice treated with the KS-133/KS-487 nanoparticles exhibited significant improvements in cognitive functions, as demonstrated by novel object recognition tests. These improvements were attributed to the inhibition of VIPR2.

Dr. Miyako emphasized the real-world potential of the study, noting that existing drugs primarily rely on neurotransmitter modulation, limiting their effectiveness for cognitive dysfunction. He suggested that their peptide formulation could serve as a novel drug to restore cognitive function in schizophrenia.

In conclusion, the study conducted by Dr. Miyako and his colleagues offers preclinical evidence supporting a new therapeutic strategy that targets VIPR2 to improve cognitive impairment in schizophrenia. Dr. Miyako expressed optimism about the future, stating, "We will extend our study to involve cells and animal models, as well as human clinical trials, to confirm the efficacy and safety of this peptide formulation and promote its development as a new treatment for schizophrenia within 5 years." The study's findings hold promise for the development of more effective treatment options for schizophrenia, especially in addressing cognitive impairments.