A positive allosteric modulator of mGluR5 promotes neuroprotective effects in mouse models of Alzheimer's disease.

Abstract

Alzheimer's Disease (AD) is the most prevalent neurodegenerative disorder. Despite advances in the understanding of its pathophysiology, none of the available therapies prevents disease progression. Excess glutamate plays an important role in excitotoxicity by activating ionotropic receptors. However, the mechanisms modulating neuronal cell survival/death via metabotropic glutamate receptors (mGluRs) are not completely understood. Recent data indicates that CDPPB, a positive allosteric modulator of mGluR5, has neuroprotective effects. Thus, this work aimed to investigate CDPPB treatment effects on amyloid-β (Aβ) induced pathological alterations in vitro and in vivo and in a transgenic mouse model of AD (T41 mice). Aβ induced cell death in primary cultures of hippocampal neurons, which was prevented by CDPPB. Male C57BL/6 mice underwent stereotaxic surgery for unilateral intra-hippocampal Aβ injection, which induced memory deficits, neurodegeneration, neuronal viability reduction and decrease of doublecortin-positive cells, a marker of immature neurons and neuronal proliferation. Treatment with CDPPB for 8 days reversed neurodegeneration and doublecortin-positive cells loss and recovered memory function. Fourteen months old T41 mice presented cognitive deficits, neuronal viability reduction, gliosis and Aβ accumulation. Treatment with CDPPB for 28 days increased neuronal viability (32.2% increase in NeuN+ cells) and reduced gliosis in CA1 region (Iba-1+ area by 31.3% and GFAP+ area by 37.5%) in transgenic animals, without inducing hepatotoxicity. However, it did not reverse cognitive deficit. Despite a four-week treatment did not prevent memory loss in aged transgenic mice, CDPPB is protective against Aβ stimulus. Therefore, this drug represents a potential candidate for further investigations as AD treatment.

• Authors: Paula Maria Quaglio Bellozi, Giovanni Freitas Gomes, Maria Carolina Machado da Silva, Isabel Vieira de Assis Lima, Carla Ribeiro Álvares Batista, Wellerson de Oliveira Carneiro Junior, Juliana Guimarães Dória, Érica Leandro Marciano Vieira, Rafael Pinto Vieira, Rossimiriam Pereira de Freitas, Claudia Natália Ferreira, Eduardo Candelario-Jalil, Tony Wyss-Coray, Fabíola Mara Ribeiro, Antônio Carlos Pinheiro de Oliveira
• Journal: Neuropharmacology (Neuropharmacology) Vol. 160 Pg. 107785 (12 01 2019) ISSN: 1873-7064 [Electronic] England
• PMID: 31541651 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.

Chemical References

• 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide
• Amyloid beta-Peptides
• Benzamides
• Grm5 protein, mouse
• Neuroprotective Agents
• Peptide Fragments
• Pyrazoles
• Receptor, Metabotropic Glutamate 5
• amyloid beta-protein (1-42)

Topics

• Allosteric Regulation
• Alzheimer Disease (drug therapy)
• Amyloid beta-Peptides (adverse effects)
• Animals
• Benzamides (administration & dosage, pharmacology)
• Disease Models, Animal
• Hippocampus (drug effects)
• Male
• Memory (drug effects)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Neurodegenerative Diseases (chemically induced, drug therapy)
• Neurons (drug effects)
• Neuroprotective Agents (administration & dosage, pharmacology)
• Peptide Fragments (adverse effects)
• Pyrazoles (administration & dosage, pharmacology)
• Receptor, Metabotropic Glutamate 5 (drug effects, metabolism)