PETを用いて、慢性社会的敗北ストレス(SDS)モデルマウスにおけるシクロオキシゲナーゼ(COX)-1とToll-like receptor(TLR)4の分布の時間変化を調べた。COX-1 PETでは、COX-1のPETプローブの(S)-[18F]KTP-Meを使用した。大脳皮質、海馬、線条体、視床を含む脳の広範部位に亜慢性SDSで一時的に取り込まれ、ゆっくりと消失した。TLR4 PETでは新しい血液脳関門透過性PETプローブ[11C1]を開発した。小脳では亜慢性と慢性のSDS後に、橋-延髄では慢性SDS後に11C1の消失が促進された。

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

Despite the recognized roles of neuroinflammation in mental illnesses, PET imaging on currently available biomarkers has limitations due to the lack of evidence demonstrating their relationship to the molecular and cellular events of inflammation associated with the pathology of mental illness. Rodent stress models, such as chronic social defeat stress (SDS), have identified crucial roles for COX-1 and TLR4, which are innate immune molecules, in chronic SDS-induced neuroinflammation and its behavioral consequences. In this study, we performed COX-1 and TLR4 PET imaging at multiple time points during chronic SDS in mice. For COX-1 PET imaging, we used the COX-1 PET probe (S)-[18F]KTP-Me. Subchronic SDS transiently increased uptake and slower washout in broad regions of the brain, including the cerebral cortex, hippocampus, striatum, and thalamus. For TLR4 PET imaging, we developed a new BBB-permeable PET probe, [11C]1, which detected LPS-induced neuroinflammation. Washout of [11C]1 was facilitated in the cerebellum after subchronic and chronic SDS and in the pons-medulla after chronic SDS. Collectively, our findings suggest the potential usefulness of COX-1 and TLR4 PET imaging in visualizing and understanding time-dependent process of neuroinflammation in stress-related mental illnesses.

DOI： 10.1016/j.jphs.2025.01.006

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Chemogenetic approaches employing ligand-gated ion channels are advantageous regarding manipulation of target neuronal population functions independently of endogenous second messenger pathways. Among them, Ionotropic Receptor (IR)-mediated neuronal activation (IRNA) allows stimulation of mammalian neurons that heterologously express members of the insect chemosensory IR repertoire in response to their cognate ligands. In the original protocol, phenylacetic acid, a ligand of the IR84a/IR8a complex, was locally injected into a brain region due to its low permeability of the blood-brain barrier. To circumvent this invasive injection, we sought to develop a strategy of peripheral administration with a precursor of phenylacetic acid, phenylacetic acid methyl ester, which is efficiently transferred into the brain and converted to the mature ligand by endogenous esterase activities. This strategy was validated by electrophysiological, biochemical, brain-imaging, and behavioral analyses, demonstrating high utility of systemic IRNA technology in the remote activation of target neurons in the brain.

DOI： 10.1038/s42003-024-06223-4

PubMed

Publishing type：Research paper (scientific journal)  

<jats:title>Abstract</jats:title>
<jats:p>Transient receptor potential cation channel subfamily V member 1 (TRPV1) was identified using capsaicin, a pungent compound that is present in red pepper. The activation of TRPV1 induces an influx of calcium ions into cells and causes excitation of sensory neurons, associating with thermal sensing, sweating and pain. TRPV1 is also identified in various types of cancer cells. The expression of TRPV1 in cancer cells depends on the type of cancer and the stage of the disease. Therefore, TRPV1 has been considered a potential target of medicinal chemistry for drug development, and blocking its activation may lead to cancer therapy and pain relief. However, the details of the pathophysiological function of TRPV1 in vivo are still unclear. To explore practical use of TRPV1, we focused on positron emission tomography imaging and developed a 11C-radiolabeled tracer to visualize TRPV1.</jats:p>

DOI： 10.1093/jjco/hyad194

PubMed