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Novel peptide formulation shows promise of treating cognitive decline in schizophrenia

The nanoparticle-based drug delivery system, developed by researchers from Japan, can specifically target genetic mechanisms associated with schizophrenia

Date:
June 27, 2024
Source:
Japan Advanced Institute of Science and Technology
Summary:
Schizophrenia is a serious mental health disorder linked to the imbalance of chemical neurotransmitters that affect cognitive capabilities. Current therapies against schizophrenia have numerous limitations, largely due to the selective permeability of blood-brain barrier, which necessitates the development of novel strategies.
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Schizophrenia is a complicated mental health disorder accompanied by wide range of symptoms such as hallucinations, impaired cognitive ability, and disorganized speech or behavior. It has been associated with anomalies in neurotransmission due to the imbalance of chemical neurotransmitters. Current treatment strategies against schizophrenia involve the administration of antipsychotic drugs, which can cause adverse effects and are associated with a high risk of cardiovascular disease. Moreover, in patients, response to therapeutic drugs is often inadequate as the blood-brain barrier (BBB), a protective barrier of cells, strictly regulates the movement of ions and molecules into the brain.

To overcome the hurdle of BBB and facilitate the transport of therapeutic drugs into brain tissue to treat schizophrenia, researchers have explored the applicability of receptor-mediated transcytosis (RMT) using low-density lipoprotein receptor-related protein 1 (LRP1). This research was conducted by team led by Associate Professor Eijiro Miyako from Japan Advanced Institute of Science and Technology (JAIST), included Prof. Yukio Ago from Hiroshima University, Prof. Shinsaku Nakagawa from Osaka University, Prof. Takatsugu Hirokawa from Tsukuba University, and Dr. Kotaro Sakamoto, Senior Principal Scientist at Ichimaru Pharcos Co., Ltd. Their study was published in JACS Au journal on June 20, 2024.

The researchers were inspired by previous findings which showed the interactions of vasoactive intestinal peptide receptor 2 (VIPR2) gene duplication in schizophrenia and their own discovery of a novel peptide, KS-133. The novel peptide, KS-133, has selective antagonist activity to VIPR2, leading to its downregulation. However, the major limitation associated with KS-133 was its poor permeability across BBB.

To facilitate the effective transport of KS-133 into the brain, they developed a brain-targeting peptide, KS-487, that could specifically bind to LRP1 and influence RMT. Finally, the researchers developed a novel nanoparticle-based drug delivery system (DDS) where KS-133 peptide was encapsulated with KS-487 targeting peptide and studied its efficacy in treating schizophrenia.

The administration of peptide formulations via the DDS resulted in the effective distribution of the drug in the brains of mice. Drug release profiles assessed by pharmacokinetic analysis confirmed the role of the brain-targeting peptide in transporting KS-133 into the brain. Furthermore, the efficacy of DDS was evaluated in mice with induced schizophrenia by elevated activation of VIPR2. Mice treated with KS-133/KS-487 nanoparticles showed significant improvement in cognitive functions during novel object recognition tests, which could be attributed to the inhibition of VIPR2.

Explaining the real-life applications and potential of their study, Dr. Miyako shares, "Existing drugs only have mechanisms involving neurotransmitter modulation, and their therapeutic effects are limited, especially for cognitive dysfunction. Thus, our peptide formulation could be used as a novel drug to restore cognitive dysfunction in schizophrenia."

In summary, this study by Dr. Miyako and co-researchers provides preclinical evidence of a novel therapeutic strategy for targeting VIPR2 that could improve cognitive impairment in schizophrenia. "Going ahead, 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," concludes Dr. Miyako, optimistic about the long-term implications of their study.


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Materials provided by Japan Advanced Institute of Science and Technology. Note: Content may be edited for style and length.


Journal Reference:

  1. Kotaro Sakamoto, Seigo Iwata, Zihao Jin, Lu Chen, Tatsunori Miyaoka, Mei Yamada, Kaiga Katahira, Rei Yokoyama, Ami Ono, Satoshi Asano, Kotaro Tanimoto, Rika Ishimura, Shinsaku Nakagawa, Takatsugu Hirokawa, Yukio Ago, Eijiro Miyako. Cyclic Peptides KS-133 and KS-487 Multifunctionalized Nanoparticles Enable Efficient Brain Targeting for Treating Schizophrenia. JACS Au, 2024; DOI: 10.1021/jacsau.4c00311

Cite This Page:

Japan Advanced Institute of Science and Technology. "Novel peptide formulation shows promise of treating cognitive decline in schizophrenia." ScienceDaily. ScienceDaily, 27 June 2024. <www.sciencedaily.com/releases/2024/06/240627172219.htm>.
Japan Advanced Institute of Science and Technology. (2024, June 27). Novel peptide formulation shows promise of treating cognitive decline in schizophrenia. ScienceDaily. Retrieved July 17, 2024 from www.sciencedaily.com/releases/2024/06/240627172219.htm
Japan Advanced Institute of Science and Technology. "Novel peptide formulation shows promise of treating cognitive decline in schizophrenia." ScienceDaily. www.sciencedaily.com/releases/2024/06/240627172219.htm (accessed July 17, 2024).

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