In Vivo Monitoring for Regional Changes of Metabotropic Glutamate Receptor Subtype 1 (mGluR1) in Pilocarpine-Induced Epileptic Rat Brain by Small-Animal PET

Tomoteru Yamasaki,Lin Xie,Ming-Rong Zhang,Akiko Hatori,Masayuki Fujinaga,Wakana Mori,Nobuki Nengaki,Hidekatsu Wakizaka,Yiding Zhang

doi:10.1038/s41598-017-15015-2

Abstract

Metabotropic glutamate receptor subtype 1 (mGluR1) is a crucial pharmacological target for several central nervous system disorders. In this study, we aimed to monitor in vivo regional changes of mGluR1 related to neuroinflammation in the brains of rats after pilocarpine-induced status epilepticus (PISE) using longitudinal positron emission tomography (PET). PISE was induced in rats by administering lithium chloride, followed by repeated pilocarpine hydrochloride treatments. PET assessments were conducted using N-[4-[6-(isopropylamino)-pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methyl-4-[11C]methylbenzamide ([11C]ITDM), a selective radioligand for mGluR1, and N-benzyl-N-[11C]methyl-2-(7-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl)acetamide ([11C]DAC), a selective translocator protein PET ligand for neuroinflammation monitoring. PET scans were conducted on PISE rats at 1 day (acute), 1 week (subacute) and 3 weeks (chronic) after repeated seizures. PET with [11C]ITDM showed significant decreases of mGluR1 availability (BPND) in the thalamus and hippocampus after PISE over the chronic period. Conversely, PET with [11C]DAC exhibited a significant increase of radioactive uptake in the forebrain after the acute period, especially in the thalamus. These conflicting changes in the thalamus indicated negative correlation. In conclusion, PET with [11C]ITDM could successfully visualize hippocampal and thalamic declines of mGluR1 related to neuroinflammation, which would help further understanding for mGluR1 functions in neuroexcitotoxicity.

Highlights

Metabotropic glutamate receptor subtype 1 is a crucial pharmacological target for several central nervous system disorders
We aimed to monitor in vivo regional changes of Metabotropic glutamate receptor subtype 1 (mGluR1) related to neuroinflammation in the brains of rats after pilocarpine-induced status epilepticus (PISE) using longitudinal positron emission tomography (PET)
It has been reported that immunoreactivity for hippocampal mGluR1α, which is one of three mGluR1 splice variants, shows a marked decrease 1 day after PISE, and that mGluR1α-immunoreactive dendrites and cell bodies gradually reappear between 3 and 31 days after PISE15

Summary

Introduction

Metabotropic glutamate receptor subtype 1 (mGluR1) is a crucial pharmacological target for several central nervous system disorders. MGluR1 and mGluR5 (belonging to group I) stimulate polyphosphoinositide hydrolysis via activation of phospholipase C This induces the production of second messengers such as inositol 1,4,5-triphosphate and diacylglyceol[2]. A recent pilot positron emission tomography (PET) imaging study has been performed using [11C]ABP688, a widely used PET ligand for mGluR5 in preclinical and clinical studies[6,7], in rats after pilocarpine-induced status epilepticus (PISE)[8]. Our research group has developed a useful new PET ligand to image mGluR1 called as N-[4-[6(isopropylamino)-pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methyl-4-[11C]methylbenzamide ([11C]ITDM). This ligand has high bind affinity (Ki = 13.6 nM) and selectivity for mGluR19. [11C]ITDM-PET allows quantification of slight changes in mGluR1 density in experimental animal models of CNS disorders, such as Huntington’s disease and Parkinson’s disease[10,11]

Objectives

Methods

Results

Conclusion