An exploratory clinical study of p38<i>α</i> kinase inhibition in Alzheimer's disease

Scheltens, Philip; Prins, Niels D.; Lammertsma, Adriaan A.; Yaqub, Maqsood; Gouw, Alida A.; Wink, Alle Meije; Chu, Hui May; Berckel, Bart N.M. van; Alam, John

doi:10.1002/acn3.549

Cited by 46 publications

(26 citation statements)

References 34 publications

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“…Recent reports using selective p38α MAPK inhibitors, neflamapimod (VX-745), MW150, and MW181, have shown potential therapeutic effects for AD. 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].…”

Section: Njk14047 Decreases Neurotoxicity Mediated By the Activated Mmentioning

confidence: 99%

“…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]. These results suggest that p38α/β MAPKs are potentially important targets in AD therapeutics, and thus, their inhibitors may be promising drugs.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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Background: Chronic neuroinflammation, aggressive amyloid beta (Aβ) deposition, neuronal cell loss, and cognitive impairment are pathological presentations of Alzheimer's disease (AD). Therefore, resolution of neuroinflammation and inhibition of Aβ-driven pathology have been suggested to be important strategies for AD therapy. Previous efforts to prevent AD progression have identified p38 mitogen-activated protein kinases (MAPKs) as a promising target for AD therapy. Recent studies showed pharmacological inhibition of p38α MAPK improved memory impairment in AD mouse models. Methods: In this study, we used an AD mouse model, 5XFAD, to explore the therapeutic potential of NJK14047 which is a novel, selective p38α/β MAPK inhibitor. The mice were injected with 2.5 mg/kg NJK14047 or vehicle every other day for 3 months. Morris water maze task and histological imaging analysis were performed. Protein and mRNA expression levels were measured using immunoblotting and qRT-PCR, respectively. In vitro studies were conducted to measure the cytotoxicity of microglia-and astrocyte-conditioned medium on primary neurons using the MTT assay and TUNEL assay. Results: NJK14047 treatment downregulated phospho-p38 MAPK levels, decreased the amount of Aβ deposits, and reduced spatial learning memory loss in 9-month-old 5XFAD mice. While the pro-inflammatory conditions were decreased, the expression of alternatively activated microglial markers and microglial phagocytic receptors was increased. Furthermore, NJK14047 treatment reduced the number of degenerating neurons labeled with Fluoro-Jade B in the brains of 5XFAD mice. The neuroprotective effect of NJK14047 was further confirmed by in vitro studies.

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Section: Njk14047 Decreases Neurotoxicity Mediated By the Activated Mmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…demonstrated that neflamapimod penetrates the blood-brain barrier in humans and exhibits diseaserelevant pharmacological activity in the brain [45,46].…”

Section: Pagementioning

confidence: 99%

“…The clinical science translational opportunity with neflamapimod is that the compound has already been studied in early Alzheimer's disease patients at the human dose equivalents of 1.5 and 4.5 mg/kg in the rat [46]. These doses were well-tolerated, achieved target cerebral spinal fluid (CSF) drug levels consistent with robust blood-brain-barrier penetration, and demonstrated target activity as assessed by imaging and CSF biomarkers.…”

Section: Page 35mentioning

confidence: 99%

Continuous administration of the p38α inhibitor neflamapimod 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

Krakovsky¹,

Germann²,

Levy³

2020

Preprint

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There is unmet need for effective stroke therapies. Numerous neuroprotection attempts for acute cerebral ischemia have failed and there is growing interest in developing therapies that widen the treatment initiation window and promote functional recovery through increasing synaptic plasticity. The p38 mitogen-activated protein kinase is an already proven target for acute experimental stroke intervention and was hypothesized to also contribute to neuroinflammationmediated impairment of recovery during the subacute phase. Neflamapimod, an orally bioavailable, brain-penetrant, potent and selective small molecule p38 inhibitor was evaluated as a subacute phase stroke treatment to promote recovery in this research study. Neflamapimod administration at two clinically relevant dose levels was initiated outside of the previously characterized neuroprotection window of less than 24 hours after stroke for p38 inhibitors to rats after transient middle cerebral artery occlusion. Continuous administration of neflamapimod, starting at 48 hours after reperfusion, significantly improved behavioral outcomes assessed by the modified neurological severity score at four-and six-weeks post stroke in a dose-dependent manner. Neflamapimod also demonstrated beneficial effects on additional measures of sensory and motor function and resulted in a dose-related increase in the terminal brain-derived neurotrophic factor protein level in both the injured and uninjured brain hemisphere. Variable interleukin-1 levels were detected in the injured brain hemisphere at study termination in a subset of the animals within every test group, implying ongoing, chronic inflammation, however, no clear neflamapimod effect on interleukin-1 production was observable. The dose-related in vivo efficacy of neflamapimod offers the possibility of both expanding the window for initiation of therapy after stroke and for improving recovery after a completed stroke. Since neflamapimod is already in mid-stage clinical trials for Alzheimer's disease PAGE 3 and related dementias, the current results make it especially attractive for evaluation in a proof-ofconcept clinical trial as therapeutic to promote recovery after ischemic stroke.

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“…Importantly, this work identifies a new, druggable target that could be used to block synaptotoxic sequelae in prion diseases: p38 MAPK. Inhibitors of this kinase are already in clinical use for the treatment of inflammatory and neurodegenerative disorders (including Alzheimer's disease) , and some of these compounds might be easily repurposed for therapy of prion diseases. The neuronal culture system described here could be readily adapted to screen additional therapeutic agents, as we have already done for some novel anti‐PrP Sc compounds .…”

Section: A Novel Neuronal Culture System To Study Prion Neurotoxicitymentioning

confidence: 99%

Prion neurotoxicity

2019

Brain Pathology

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Although the mechanisms underlying prion propagation and infectivity are now well established, the processes accounting for prion toxicity and pathogenesis have remained mysterious. These processes are of enormous clinical relevance as they hold the key to identification of new molecular targets for therapeutic intervention. In this review, we will discuss two broad areas of investigation relevant to understanding prion neurotoxicity. The first is the use of in vitro experimental systems that model key events in prion pathogenesis. In this context, we will describe a hippocampal neuronal culture system we developed that reproduces the earliest pathological alterations in synaptic morphology and function in response to PrP Sc . This system has allowed us to define a core synaptotoxic signaling pathway involving the activation of NMDA and AMPA receptors, stimulation of p38 MAPK phosphorylation and collapse of the actin cytoskeleton in dendritic spines. The second area concerns a striking and unexpected phenomenon in which certain structural manipulations of the PrP C molecule itself, including introduction of N-terminal deletion mutations or binding of antibodies to C-terminal epitopes, unleash powerful toxic effects in cultured cells and transgenic mice. We will describe our studies of this phenomenon, which led to the recognition that it is related to the induction of large, abnormal ionic currents by the structurally altered PrP molecules. Our results suggest a model in which the flexible N-terminal domain of PrP C serves as a toxic effector which is regulated by intramolecular interactions with the globular C-terminal domain. Taken together, these two areas of study have provided important clues to underlying cellular and molecular mechanisms of prion neurotoxicity. Nevertheless, much remains to be done on this next frontier of prion science.

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An exploratory clinical study of p38α kinase inhibition in Alzheimer's disease

Cited by 46 publications

References 34 publications

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

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

Continuous administration of the p38α inhibitor neflamapimod 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

Prion neurotoxicity

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