Continuous administration of a p38α inhibitor during the subacute phase after transient ischemia-induced stroke in the rat promotes dose-dependent functional recovery accompanied by increase in brain BDNF protein level

Abstract

There is unmet need for effective stroke therapies. Numerous neuroprotection attempts for acute cerebral ischemia have failed and as a result there is growing interest in developing therapies to promote functional recovery through increasing synaptic plasticity. For this research study, we hypothesized that in addition to its previously reported role in mediating cell death during the acute phase, the alpha isoform of p38 mitogen-activated protein kinase, p38α, may also contribute to interleukin-1β-mediated impairment of functional recovery during the subacute phase after acute ischemic stroke. Accordingly, an oral, brain-penetrant, small molecule p38α inhibitor, neflamapimod, was evaluated as a subacute phase stroke treatment to promote functional recovery. Neflamapimod administration to rats after transient middle cerebral artery occlusion at two dose levels was initiated outside of the previously characterized therapeutic window for neuroprotection of less than 24 hours for p38α inhibitors. Six-week administration of neflamapimod, starting at 48 hours after reperfusion, significantly improved behavioral outcomes assessed by the modified neurological severity score at Week 4 and at Week 6 post stroke in a dose-dependent manner. Neflamapimod demonstrated beneficial effects on additional measures of sensory and motor function. It also resulted in a dose-related increase in brain-derived neurotrophic factor (BDNF) protein levels, a previously reported potential marker of synaptic plasticity that was measured in brain homogenates at sacrifice. Taken together with literature evidence on the role of p38α-dependent suppression by interleukin-1β of BDNF-mediated synaptic plasticity and BDNF production, our findings support a mechanistic model in which inhibition of p38α promotes functional recovery after ischemic stroke by blocking the deleterious effects of interleukin-1β on synaptic plasticity. The dose-related in vivo efficacy of neflamapimod offers the possibility of having a therapy for stroke that could be initiated outside the short time window for neuroprotection and for improving recovery after a completed stroke.

Transcriptomic Profiling Reveals Discrete Poststroke Dementia Neuronal and Gliovascular Signatures

“…Interleukin-1 (IL1) is a family of major proinflammatory cytokines, with IL1β previously connected to the neurodegenerative effect of neuroinflammation on cognition and synaptic plasticity in the brain [36]. Chronic elevation of IL1β suppresses BDNF and is a potential therapeutic target in the treatment and recovery from ischaemic stroke [37]. This concept is corroborated in the current study with the upregulation of another IL1 cytokine, IL1α and corresponding downregulation of BDNF in PSD neurons.…”

Preclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration

“…First, neflamapimod reversed deficits in Morris water maze performance 23 , attributed to basal forebrain dysfunction 42 , in aged rats. Second, neflamapimod improved functional recovery after a transient-ischemia induced stroke in rats 43 , with basal forebrain cholinergic function regarded as rate-limiting for the recovery process 44 . Together with these previously reported findings, the effects of neflamapimod in Ts2 mice provide preclinical proof-of-concept for p38α inhibition to reverse BFCN dysfunction.…”

Is Immune Suppression Involved in the Ischemic Stroke? A Study Based on Computational Biology

“…p38 mitogenactivated protein kinase (MAPK) signaling is a key mediator of inflammation, being a critical mediator of cell responses to cytokines and MAPK signaling has been widely implicated in the pathogenesis of stroke (Sun and Nan, 2016), although the specific upstream and downstream mechanisms remain unclarified, and different brain tissue types are marked by varying MAPK signaling patterns after ischemic stroke (Sawe et al, 2008). Animal data have shown that inhibition of p38 MAPKα starting in the early period after stroke led to improvement in motor and somatosensory function (Alam et al, 2020), whereas others have reported that MAPK-1 signaling plays an endogenous protective role in stroke and its inhibition accelerated strokeinduced injury via its anti-apoptotic and anti-inflammatory actions (Liu et al, 2014). MAPK inhibitors are emerging as promising anti-inflammatory agents for acute stages of brain inflammation (Kaminska et al, 2009) including cerebrovascular disorders (Ansar et al, 2013).…”