Aminopyridazines Attenuate Hippocampus-Dependent Behavioral Deficits Induced by Human β-Amyloid in a Murine Model of Neuroinflammation

Abstract

The importance of glial cell-driven neuroinflammation in the pathogenesis and progression of Alzheimer's disease (AD) led us to initiate a drug discovery effort targeting the neuroinflammatory cycle that is characteristic of AD. We used our synthetic chemistry platform focused on bioavailable aminopyridazines as a new chemotype for AD drug discovery to develop novel, selective suppressors of key inflammatory and oxidative pathways in glia. We found that MW01-070C, an aminopyridazine that works via mechanisms distinct from NSAIDs and p38 MAPK inhibitors, attenuates beta-amyloid (Abeta)-induced neuroinflammation and neuronal dysfunction in a dose-dependent manner, and prevents Abeta-induced behavioral impairment. In vivo data were obtained with a murine model that uses intraventricular infusion of human Abeta1-42 peptide and replicates many of the hallmarks of AD pathology, including neuroinflammation, neuronal and synaptic degeneration, and amyloid deposition. The quantifiable endpoint pathology is robust, reproducible, and rapid in onset. Our results provide a proof of concept that targeting neuroinflammation with aminopyridazines is a viable AD drug discovery approach that has the potential to modulate disease progression and document the utility of this mouse model for preclinical screening of compounds targeting AD-relevant neuroinflammation and neuronal death.

Glia as a Therapeutic Target: Selective Suppression of Human Amyloid-β-Induced Upregulation of Brain Proinflammatory Cytokine Production Attenuates Neurodegeneration

“…Once daily treatment began at day 21 after start of A␤ ICV infusion and continued for 14 d. Beginning at day 50 after start of A␤ ICV infusion, the Y maze test of spontaneous alternation was used to evaluate hippocampus-dependent spatial learning as described previously (Craft et al, 2004a). Briefly, each mouse was placed in the start arm and then released to choose one of the two other arms.…”

“…An essential aspect of testing these hypotheses is showing that a selective suppressor of increased proinflammatory cytokine production by activated glia can selectively attenuate proinflammatory cytokine production and neurophysiological injury endpoints induced by a disease-relevant stimulus in vivo. Therefore, MW01-5-188WH was tested for efficacy in a mouse assay of human A␤-induced neuroinflammation with neurodegeneration outcomes, including synaptic dysfunction, neuronal death, and hippocampus-dependent behavioral deficits (Craft et al, 2004a(Craft et al, ,b, 2005a. This model has high phenotypic penetrance of pathophysiology endpoints and uses infusion of human A␤, not amyloid precursor protein (APP).…”

“…Clinical and preclinical studies revealed a previously underappreciated role of excessive glial activation, or neuroinflammation, in the pathophysiology of these progressive neurodegenerative disorders (Griffin et al, 1989(Griffin et al, , 1998Wright, 2002;Craft et al, 2005a,b,c;Miller, 2005;Tuppo and Arias, 2005;Weydt and Moller, 2005) and raised the hypothesis that targeting of neuroinflammation might be a therapeutic approach to altering disease progression (Frautschy et al, 2001;Jantzen et al, 2002;Yan et al, 2003;Craft et al, 2004aCraft et al, ,b, 2005c. However, most investigations testing this hypothesis used drugs approved for other clinical indications or developed using approaches that did not have suppression of glia activation as the primary focus, yielding mixed results (Aisen et al, 2003;Breitner, 2003;Cole et al, 2004;Reines et al, 2004).…”

Validation of the Neuroinflammation Cycle as a Drug Discovery Target Using Integrative Chemical Biology and Lead Compound Development with an Alzheimers Disease-Related Mouse Model

“…Recently, we initiated a concerted effort to address unmet needs in AD based on an internal chemistry platform †Address correspondence to this author at the Northwestern University Feinberg Medical School, 303 E. Chicago Ave, , Chicago, IL 60611-3008, USA; Tel: 312-503-0656; Fax: 312-503-0007; E-mail: mwatterson@northwestern.edu *These authors contributed equally to this work. centered around new bioavailable protein kinase inhibitors and an unbiased biological platform using a hierarchal assay decision tree [2][3][4][5][6]. The goal of the investigation is to test the hypothesis that the neuroinflammation cycle might be a point of intervention for altering disease progression.…”

“…Tests of our compounds in the newly developed animal model allowed discovery of novel synthetic inhibitors with in vivo efficacy and endpoint specificity in hippocampus biopsy analyses that are consistent with their in vitro, cell based activities. For example, this phase of our integrative chemical biology approach showed [5,6] that intervention in vivo with MW01-070C could attenuate Aβ-induced glial activation, provide hippocampal neuroprotection, decrease brain amyloid load, and prevent hippocampal-dependent behavioral deficits in the mouse model of AD-relevant neuroinflammation. Specifically, intracerebroventricular infusion of human Aβ1-42 increased the number of activated astrocytes and microglia and the levels of the proinflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor α (TNFα) and S100B in the hippocampus.…”