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A selective p38α/β MAPK inhibitor alleviates neuropathology and cognitive impairment, and modulates microglia
Min Sung Gee1, Seung Hwan Son1, Seung Ho Jeon1
1Department of Fundamental Pharmaceutical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea.
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.
Conclusion:
Taken together, a selective p38α/β MAPK inhibitor NJK14047 successfully showed therapeutic effects for AD in 5XFAD mice. Based on our data, p38 MAPK inhibition is a potential strategy for AD therapy, suggesting NJK14047 as one of the promising candidates for AD therapeutics targeting p38 MAPKs.
Insights
NJK14047, a selective p38α/β MAPK inhibitor, reduced Alzheimer's disease (AD) pathology and improved memory in a mouse model. This study highlights p38 MAPK inhibition as a promising therapeutic strategy for AD.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Alzheimer's disease (AD) is characterized by neuroinflammation, amyloid beta (Aβ) deposition, neuronal loss, and cognitive decline.
- Resolving neuroinflammation and inhibiting Aβ pathology are key therapeutic strategies for AD.
- p38 mitogen-activated protein kinases (MAPKs) are identified as promising therapeutic targets for AD, with p38α MAPK inhibition showing memory improvement in AD models.
Purpose of the Study:
- To explore the therapeutic potential of NJK14047, a novel selective p38α/β MAPK inhibitor, in an AD mouse model.
- To investigate the effects of NJK14047 on neuroinflammation, Aβ deposition, and cognitive function in 5XFAD mice.
Main Methods:
- Utilized the 5XFAD AD mouse model, administering NJK14047 or vehicle every other day for 3 months.
- Assessed cognitive function using the Morris water maze task and analyzed brain pathology via histological imaging.
- Quantified protein and mRNA expression levels using immunoblotting and qRT-PCR, respectively.
- Conducted in vitro studies to evaluate the neuroprotective effects of NJK14047.
Main Results:
- NJK14047 treatment decreased phospho-p38 MAPK levels and reduced Aβ deposits and spatial learning memory loss in 5XFAD mice.
- Pro-inflammatory markers were downregulated, while alternatively activated microglial markers and phagocytic receptors were upregulated.
- NJK14047 treatment decreased the number of degenerating neurons and demonstrated neuroprotective effects in vitro.
Conclusions:
- Selective p38α/β MAPK inhibition with NJK14047 demonstrated therapeutic effects in the 5XFAD AD mouse model.
- p38 MAPK inhibition represents a potential therapeutic strategy for AD.
- NJK14047 is a promising candidate for AD therapeutics targeting p38 MAPKs.
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