An isoform-selective p38α mitogen-activated protein kinase inhibitor rescues early entorhinal cortex dysfunctions in a mouse model of Alzheimer's disease

Abstract

Neuroinflammation is a fundamental mechanism in Alzheimer's disease (AD) progression. The stress-induced activation of the p38α mitogen-activated protein kinase (MAPK) leads to increased production of proinflammatory cytokines and neurodegeneration. We investigated the effects of an isoform selective p38α MAPK inhibitor, MW01-18-150SRM (MW150), administered at 2.5 mg/kg/d (i.p.; 14 days) on early entorhinal cortex (EC) alterations in an AD mouse model carrying human mutations of the amyloid precursor protein (mhAPP). We used electrophysiological analyses with long-term potentiation induction in EC-containing brain slices and EC-relevant associative memory tasks. We found that MW150 was capable of rescuing long-term potentiation in 2-month old mhAPP mice. Acute delivery of MW150 to brain slices was similarly effective in rescuing long-term potentiation, with a comparable efficacy to that of the widely used multikinase inhibitor SB203580. MW150-treated mhAPP mice demonstrated improved ability to discriminate novel associations between objects and their position/context. Our findings suggest that the selective inhibition of the stress-activated p38α MAPK with MW150 can attenuate the EC dysfunctions associated with neuroinflammation in an early stage of AD progression.

A Selective and Brain Penetrant p38αMAPK Inhibitor Candidate for Neurologic and Neuropsychiatric Disorders That Attenuates Neuroinflammation and Cognitive Dysfunction

“…The small number of novel compounds needed to arrive at a viable clinical candidate is characteristic of fragment-based approaches, especially when the process is driven by safety and pharmacodynamic considerations inherent in secondary pharmacology outcomes. Treatment with compounds 9 – 11 or cell-selective genetic knock-down of p38αMAPK documents that inhibition of p38αMAPK can mitigate detrimental proinflammatory cytokine overproduction and neuronal/synaptic damage in a variety of animal models, 4,13−17,19,30,31 outcomes consistent with clinical observations and hypotheses. Overall, compound 11 ’s selectivity, comparative lack of prevailing off-target liabilities, and derisked pharmacology, including safety potential, make it attractive for potential use as a monotherapy or as a component of a therapeutic combination regimen for complex CNS disorders.…”

Acute Pannexin 1 Blockade Mitigates Early Synaptic Plasticity Defects in a Mouse Model of Alzheimer’s Disease

“…Perhaps the impact of reducing p38MAPK activity on the Aβ aggregation requires a more long-lasting treatment such as the p38MAPK deletion reported by Colié et al (2017). Nonetheless, its acute inhibition manages to improve LTP defects in Aβ-treated brain slices (Wang et al, 2004;Origlia et al, 2008;Rutigliano et al, 2018), supporting the idea that drugs that reduce p38MAPK activation, such as PBN ( Figure 5A), could be efficient strategies to improve synaptic defects in the AD context. Interestingly, we also observe that the inhibition of p38MAPK with SB, a drug that reportedly reverses Aβ-induced synaptic impairments in mice (Saleshando and O'Connor, 2000;Guo et al, 2017), is capable to reduce Panx1 activity in Tg hippocampal slices ( Figure 5B).…”

p38α MAPK signaling drives pharmacologically reversible brain and gastrointestinal phenotypes in the SERT Ala56 mouse

“…Repeated administration regimens of p38α MAPK inhibitors consisted of intraperitoneal, QD for 7 d before undergoing behavioral or biochemical analyses. Dosing regimens were selected based upon previous reports of p38α MAPK inhibition utilizing MW150 in vivo ( 45 , 121 ). Single administration dosing consisted of an intraperitoneal injection or either MW150 or vehicle (sterile saline) 30 min before commencement of behavioral/biochemical assay.…”