Neuroprotective effect of the alpha 7 nicotinic receptor agonist PHA 543613 in an in vivo excitotoxic adult rat model

Abstract

Neuroinflammation is a key component of the pathophysiology of neurodegenerative diseases. The link between nicotine intake and positive outcome has been established, suggesting a role played by nicotinic receptors (nAChRs), especially α7nAChRs. The objective of this study was to evaluate the potential dose effects of PHA 543613 on neuron survival and striatal microglial activation in a rat model of brain excitotoxicity. A preliminary study was performed in vitro to confirm PHA 543613 agonist properties on α7nAChRs. Rats were lesioned in the right striatum with quinolinic acid (QA) and received either vehicle or PHA 543613 at 6 or 12mg/kg twice a day until sacrifice at Day 4 post-lesion. We first compared the translocator protein quantitative autoradiography in QA-lesioned brains with [H]DPA-714 and [H]PK-11195. The effects of PHA 543613 on microglial activation and neuronal survival were then evaluated through [H]DPA-714 binding and immunofluorescence staining (Ox-42, NeuN) on adjacent brain sections. We demonstrated that [H]DPA-714 provides a better signal-to-noise ratio than [H]PK-11195. Furthermore, we showed that repeated PHA 543613 administration at a dose of 12mg/kg to QA-lesioned rats significantly protected neurons and reduced the intensity of microglial activation. This study reinforces the hypothesis that α7nAChR agonists can provide beneficial effects in the treatment of neurodegenerative diseases through potential modulation of microglial activation.

Extensive exploration of a novel rat model of Parkinson's disease using partial 6‐hydroxydopamine lesion of dopaminergic neurons suggests new therapeutic approaches

“…This bi‐directional interaction between microglia and DA neurons is known to fuel the neurodegenerative process. In our model, we quantitated the striatal density of the 18 kDa TSPO which is considered as a sensitive marker of microglial activation (Chen & Guilarte, ; Rupprecht et al, ) using [ 3 H]DPA‐714, a highly sensitive radioligand of TSPO which has demonstrated its usefulness to assess striatal microglial activation in a rat model of brain excitotoxicity (Foucault‐Fruchard et al, ). In parallel, microglial activation was assessed in the SN using immunostaining of CD11b, a surface protein which is overexpressed during activation of these cells (Roy et al, ).…”

G-Protein-Coupled Receptors in CNS: A Potential Therapeutic Target for Intervention in Neurodegenerative Disorders and Associated Cognitive Deficits

“…Another agonist, PHA 543613, attenuates early-stage HD induced by striatal quinolinic acid lesions. PHA 543613 reduced microglial activation to protect neurons [150]. In another study, α7nAChR-agonist-treated 3xTg-AD mice showed improved cognitive function [151].…”

α7 nicotinic ACh receptors are necessary for memory recovery and neuroprotection promoted by attention training in amyloid‐β‐infused mice

“…α7nAChR is a homopentameric neuronal receptor permeable to calcium ions and is one of the most frequently found ACh receptors in the CNS. Its ionotropic/metabotropic dual action has allowed the receptor's implication in memory modulation and anti‐inflammatory and neuroprotective mechanisms (Corradi & Bouzat, ; Foucault‐Fruchard et al, ; Picciotto, Higley, & Mineur, ). On the other hand, some studies have shown that the pharmacological blockade of α7nAChRs with the antagonist methyllycaconitine (MLA) produced cognitive deficits in mice (Addy, Nakajama, & Levin, ; Andriambeloson, Huyard, Poiraud, & Wagner, ).…”