Recent Advances in the Inhibition of p38 MAPK as a Potential Strategy for the Treatment of Alzheimer’s Disease

Lee, Jong Kil; Kim, Nam‐Jung

doi:10.3390/molecules22081287

Cited by 265 publications

(229 citation statements)

References 165 publications

(181 reference statements)

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“…The effect we found on episodic memory is in line with a broad scientific literature that indicates that p38 α in involved in oligomeric amyloid‐beta and inflammation‐induced synaptic dysfunction and to stress‐ and age‐related synaptic dysfunction in the hippocampus 4, 5, 10, 11, 12, 13, 14, 31. In our clinical study, the ES that we saw for immediate and delay recall compares favorably to ES of ≤0.2 for WMS immediate or delayed recall at week 12 in the placebo‐treated subjects in two trials of Souvenaid in a similar patient population (mild AD, baseline MMSE = 24) 32, 33.…”

Section: Discussionsupporting

confidence: 89%

“…The means by which p38 α kinase have been theorized to impact AD disease progression broadly fall into three categories1, 2, 3, 4, 5: (1) as an anti‐inflammatory through reducing proinflammatory cytokine production from immune cells, (2) promoting amyloid plaque clearance through modulating microglial phenotype, and (3) reversing inflammation and/or amyloid‐beta induced synaptic dysfunction, particularly impaired synaptic plasticity in the hippocampus. The first mechanism (i.e., inhibition of proinflammatory cytokine production) is the classical drug effect of p38 α kinase inhibitors that formed the basis for evaluating this class of inhibitors for rheumatoid arthritis and other peripheral inflammatory disorders.…”

Section: Discussionmentioning

confidence: 99%

“…A broad range of preclinical studies indicates that the alpha isoform of p38 mitogen‐activated protein kinase (p38 α kinase) is a robust therapeutic target for Alzheimer's disease (AD) 1, 2, 3, 4, 5. Traditionally p38 α kinase is considered to be an inflammation‐related target as microglial p38 α promotes production of proinflammatory cytokines6 and modulates microglial activation state,7, 8 and in the healthy state p38 α expression within neurons is low 9.…”

Section: Introductionmentioning

confidence: 99%

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

Scheltens

Prins

Lammertsma

et al. 2018

Ann Clin Transl Neurol

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ObjectiveThe aim of this study was to preliminarily evaluate an oral small molecule p38α kinase inhibitor in patients with early Alzheimer's disease (AD) for the effects on brain amyloid plaque load and episodic memory function, and to establish pharmacokinetic–pharmacodynamics correlations if any effects identified on these parameters.MethodsSixteen patients with early AD received a highly selective p38α inhibitor (neflamapimod) for 84 days (12 weeks). To obtain a broad range of plasma drug exposures, subjects randomized to receive either 40 mg (n = 9) or 125 mg (n = 7) twice daily. Dynamic, 11C‐PiB positron emission scans were performed at baseline and at Day 84 and quantitatively analyzed by reference parametric mapping. Episodic memory assessed as Wechsler Memory Scale (WMS) immediate and delayed recall composites.ResultIn the 11C‐PiB analyses there were no main group level effects, though in the prespecified responder analysis (>7% reduction in 11C‐PiB signal) there were three responders in the 40 mg, and one in the 125 mg group. There were statistically significant increases from baseline in mean WMS immediate recall score and WMS delayed recall at both day 28 (P = 0.03 and P = 0.001) and day 84 (P = 0.001 and P < 0.001). Individual subject plasma drug concentration profiles were significantly positively correlated with the change in combined WMS immediate and delayed recall (P < 0.0001, r 2= 0.70). Within‐subject effect size was 0.59 for immediate recall and 0.67 for delayed recall.InterpretationSelective p38α inhibition in patients with early AD may improve episodic memory and potentially impact β‐amyloid production. These preliminary clinical findings support conduct of a longer duration placebo‐controlled study, particularly to confirm the effects on episodic memory function.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Scheltens

Prins

Lammertsma

et al. 2018

Ann Clin Transl Neurol

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“…57 As a result, p38 inhibitors have recently been claimed as novel and potential therapeutics for neurodegenerative diseases. 58,59 These findings suggest that inhibition of p38 may be therapeutically effective in protecting degenerating RGCs from various pathological conditions, including glaucoma.…”

Section: Discussionmentioning

confidence: 96%

Topical Ripasudil Suppresses Retinal Ganglion Cell Death in a Mouse Model of Normal Tension Glaucoma

Akaiwa

Namekata

Azuchi

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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METHODS. Topical administration (5 lL/day) of two different concentrations of ripasudil (0.4% and 2%) were applied to EAAC1 KO mice from 5 to 12 weeks old. Optical coherence tomography, multifocal electroretinograms, the measurement of intraocular pressure (IOP), and histopathology analyses were performed at 5, 8, and 12 weeks old. Retrograde labeling of retinal ganglion cells (RGCs), immunoblot, and immunohistochemical analyses of phosphorylated p38 mitogen-activated protein kinase (MAPK) in the retina were performed at 8 weeks old.RESULTS. Topical ripasudil ameliorated retinal degeneration and improved visual function in EAAC1 KO mice at both 8 and 12 weeks old. Ripasudil reduced IOP and strongly suppressed the phosphorylation of p38 MAPK that stimulates RGC death in EAAC1 KO mice.CONCLUSIONS. These results suggest that, in addition to IOP reduction, ripasudil prevents glaucomatous retinal degeneration by neuroprotection, which is achieved by suppressing celldeath signaling pathways.

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“…The p38 kinases, in particular p38α (MAPK14), have been implicated in the pathogenesis of neurodegenerative, and pharmacological inhibitors of p38 have been shown to protect against neuronal loss in preclinical models of neurodegenerative disorders in the CNS . The basis for these studies stems from the involvement of p38 in apoptosis.…”

Section: Mitogen‐activated Protein Kinases (Mapks)mentioning

confidence: 99%

Phosphoregulation on mitochondria: Integration of cell and organelle responses

2019

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Mitochondria are highly integrated organelles that are crucial to cell adaptation and mitigating adverse physiology. Recent studies demonstrate that fundamental signal transduction pathways incorporate mitochondrial substrates into their biological programs. Reversible phosphorylation is emerging as a useful mechanism to modulate mitochondrial function in accordance with cellular changes. Critical serine/threonine protein kinases, such as the c‐Jun N‐terminal kinase (JNK), protein kinase A (PKA), PTEN‐induced kinase‐1 (PINK1), and AMP‐dependent protein kinase (AMPK), readily translocate to the outer mitochondrial membrane (OMM), the interface of mitochondria‐cell communication. OMM protein kinases phosphorylate diverse mitochondrial substrates that have discrete effects on organelle dynamics, protein import, respiratory complex activity, antioxidant capacity, and apoptosis. OMM phosphorylation events can be tempered through the actions of local protein phosphatases, such as mitogen‐activated protein kinase phosphatase‐1 (MKP‐1) and protein phosphatase 2A (PP2A), to regulate the extent and duration of signaling. The central mediators of OMM signal transduction are the scaffold proteins because the relative abundance of these accessory proteins determines the magnitude and duration of a signaling event on the mitochondrial surface, which dictates the biological outcome of a local signal transduction pathway. The concentrations of scaffold proteins, such as A‐kinase anchoring proteins (AKAPs) and Sab (or SH3 binding protein 5—SH3BP5), have been shown to influence neuronal survival and vulnerability, respectively, in models of Parkinson's disease (PD), highlighting the importance of OMM signaling to health and disease. Despite recent progress, much remains to be discovered concerning the mechanisms of OMM signaling. Nonetheless, enhancing beneficial OMM signaling events and inhibiting detrimental protein‐protein interactions on the mitochondrial surface may represent highly selective approaches to restore mitochondrial health and homeostasis and mitigate organelle dysfunction in conditions such as PD.

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Recent Advances in the Inhibition of p38 MAPK as a Potential Strategy for the Treatment of Alzheimer’s Disease

Cited by 265 publications

References 165 publications

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

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

Topical Ripasudil Suppresses Retinal Ganglion Cell Death in a Mouse Model of Normal Tension Glaucoma

Phosphoregulation on mitochondria: Integration of cell and organelle responses

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