Retention of normal glia function by an isoform-selective protein kinase inhibitor drug candidate that modulates cytokine production and cognitive outcomes

Abstract

BackgroundBrain p38α mitogen-activated protein kinase (MAPK), a potential therapeutic target for cognitive dysfunction based on the neuroinflammation-synaptic dysfunction cycle of pathophysiology progression, offers an innovative pharmacological strategy via inhibiting the same activated target in both glia and neurons, thereby enhancing the possibility for efficacy. The highly selective, brain-penetrant p38αMAPK inhibitor MW150 attenuates cognitive dysfunction in two distinct Alzheimer’s disease (AD)-relevant models and avoids the problems encountered with previous mixed-kinase inhibitor drug candidates. Therefore, it is essential that the glial effects of this CNS-active kinase inhibitor be addressed in order to anticipate future use in clinical investigations.MethodsWe explored the effects of MW150 on glial biology in the AD-relevant APP/PS1 knock-in (KI) mouse model where we previously showed efficacy in suppression of hippocampal-dependent associative and spatial memory deficits. MW150 (2.5 mg/kg/day) was administered daily to 11–12-month-old KI mice for 14 days, and levels of proinflammatory cytokines IL-1β, TNFα, and IL-6 measured in homogenates of mouse cortex using ELISA. Glial markers IBA1, CD45, CD68, and GFAP were assessed by immunohistochemistry. Microglia and amyloid plaques were quantified by immunofluorescence staining followed by confocal imaging. Levels of soluble and insoluble of Aβ40 and Aβ42 were measured by ELISA. The studies of in vivo pharmacodynamic effects on markers of neuroinflammation were complemented by mechanistic studies in the murine microglia BV2 cell line, using live cell imaging techniques to monitor proliferation, migration, and phagocytosis activities.ResultsIntervention with MW150 in KI mice during the established therapeutic time window attenuated the increased levels of IL-1β and TNFα but not IL-6. MW150 treatment also increased the IBA1+ microglia within a 15 μm radius of the amyloid plaques, without significantly affecting overall microglia or plaque volume. Levels of IBA1, CD45, CD68, GFAP, and Aβ40 and Aβ42 were not affected by MW150 treatment. MW150 did not significantly alter microglial migration, proliferation, or phagocytosis in BV2 cells.ConclusionsOur results demonstrate that MW150 at an efficacious dose can selectively modulate neuroinflammatory responses associated with pathology progression without pan-suppression of normal physiological functions of microglia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0845-2) contains supplementary material, which is available to authorized users.

A selective p38α/β MAPK inhibitor alleviates neuropathology and cognitive impairment, and modulates microglia function in 5XFAD mouse

“…Downregulation of the phospho-p38 MAPK level is related to the decreased neuroinflammation, which can reverse reactive gliosis and overexpression of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6. According to a recent study using the p38α MAPK inhibitor MW150 in the APP/PS1 mice at the age of 11 to 12 months, IL-1β and TNF-α levels were decreased; microglial cell counts were increased around the plaque [20]. Similarly, we confirmed NJK14047, reduced the pro-inflammatory cytokines, and upregulated alternatively activated microglial markers such as Arg1, YM-1, and Fizz-1 in the cortex and hippocampus of 5XFAD mice.…”

“…Neflamapimod (VX-745) improved water maze performance in aged rats [19] and enhanced episodic memory in early AD patients [21,22]. In addition, MW150 was reported to show therapeutic effects in APP/PS1 mice at the age of 11 to 12 months [20,52]. Furthermore, MW181 was suggested to reduce tau-related pathologic features and improve working memory in 20-month-old hTau mice [53].…”

“…SB203580, a traditional p38α/β MAPK inhibitor, had shown therapeutic effects in the LPS-induced depression model and AD mouse model [17,18]. Recently, two selective p38α MAPK inhibitors, neflamapimod (VX-745) and MW150, also showed therapeutic effects in aged rats and AD mouse model respectively [19,20]. The phase 2a clinical trials of neflamapimod showed improvements in episodic memory in early AD patients [21,22].…”

Stasimon Contributes to the Loss of Sensory Synapses and Motor Neuron Death in a Mouse Model of Spinal Muscular Atrophy

“…We treated SMA mice daily by intraperitoneal (i.p.) injection with either saline or 5 mg/kg of MW150-a dose previously demonstrated to effectively inhibit p38a MAPK in the CNS and to improve the phenotype of mouse models of neurological disease (Robson et al, 2018;Roy et al, 2015Roy et al, , 2019Rutigliano et al, 2018;Zhou et al, 2017). Importantly, MW150 treatment robustly decreased the levels of p53 S18 phosphorylation but not the induction of p53 in vulnerable L5 MMC SMA motor neurons relative to vehicle-treated SMA mice at P11 ( Figures 5E-5H), directly linking p38a MAPK activation to the phosphorylation of p53 S18 in SMA motor neurons.…”

Apocynin Attenuates Cobalt Chloride-Induced Pheochromocytoma Cell Apoptosis by Inhibiting P38-MAPK/Caspase-3 Pathway

“…p38 mitogen-activated protein kinases (p38-MAPK) is a mammalian orthologue of the yeast Hog1p MAPK, participating in the signaling cascade controlling cellular responses to cytokines and stress. Abnormal activity of p38 has been implicated in pathological events in several organs and tissues including the neuron, bone, lung, cardiac and skeletal muscle, red blood cells, and fetal tissues [11][12][13]. The protein product of proto-oncogene RAS can increase the activity of p38, which further induces the excessive activity of transcription factor NF-κB.…”