Functional modulation of G-protein coupled receptors during Parkinson disease-like neurodegeneration

NEUROPHARMACOLOGY

卷:108

Article

Jenkins, Bruce G.¹  Zhu, Aijun¹  Poutiainen, Pekka¹  Choi, Ji-Kyung¹  Kil, Kun-Eek¹  Zhang, Zhaoda¹  Kuruppu, Darshini²  Aytan, Nurgul³  Dedeoglu, Alpaslan^3,4  Brownell, Anna-Liisa¹ 

[1] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, 13th St, Charlestown, MA 02129 USA

[2] Massachusetts Gen Hosp, Dept Med, Surg Oncol, 55 Fruit St, Boston, MA 02114 USA

[3] VA Boston Healthcare Syst, Dept Vet Affairs, Boston, MA 02130 USA

[4] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA

关键词: Metabotropic glutamate receptor;    mGlu(4);    mGlu(5);    Parkinson's disease;    Positron emission tomography;    Pharmacological magnetic resonance imaging;   

DOI  :  10.1016/j.neuropharm.2015.11.010

来源: Elsevier

【 摘 要 】

G-protein coupled dopamine and metabotropic glutamate receptors (mGlu) can modulate neurotransmission during Parkinson's disease (PD)-like neurodegeneration. PET imaging studies in a unilateral dopamine denervation model (6-OHDA) showed a significant inverse correlation of presynaptic mGlu(4) and postsynaptic mGlu(5) expression in the striatum and rapidly declining mGlu(4) and enhanced mGlu(5) expression in the hippocampus during progressive degeneration over time. Immunohistochemical studies verified the decreased mGlu(4) expression in the hippocampus on the lesion side but did not show difference in mGlu(5) expression between lesion and control side. Pharmacological MRI studies showed enhanced hemodynamic response in several brain areas on the lesion side compared to the control side after challenge with mGlu(4) positive allosteric modulator or mGlu(5) negative allosteric modulator. However, mGlu(4) response was biphasic having short enhancement followed by negative response on both sides of brain. Studies in mGlu(4) expressing cells demonstrated that glutamate induces cooperative increase in binding of mGlu(4) ligands especially at high glutamate levels consistent with in vivo concentration. This suggests that mGlu allosteric modulators as drug candidates will be highly sensitive to changes in glutamate concentration and hence metabolic state. These experiments demonstrate the importance of the longitudinal imaging studies to investigate temporal changes in receptor functions to obtain individual response for experimental drugs. (C) 2015 Elsevier Ltd. All rights reserved.

【 授权许可】

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