Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, associated with oxidative stress, neuronal apoptosis, and the accumulation of amyloid-β (Aβ) plaques. Despite advances in understanding AD pathology, effective treatments remain limited. This study aimed to investigate the therapeutic efficacy and underlying molecular mechanisms of MK886, a selective inhibitor of the 5-lipoxygenase pathway, in the context of AD. Network pharmacology analyses were employed to evaluate MK886's potential as a treatment for AD, revealing promising interactions with key molecular targets implicated in the disease. In vitro experiments demonstrated that MK886 effectively mitigated Aβ1-42 oligomer-induced oxidative stress, apoptosis, and ferroptosis in mouse hippocampal neuronal cells (HT22). These effects were validated using techniques such as immunofluorescence, JC-1 staining, TUNEL staining, and flow cytometry. In vivo studies involved administering MK886 to APPswe/PS1dE9 (APP/PS1) mice, which resulted in significant improvements in cognitive and emotional functions as assessed by the Y-maze and Morris water maze tests. Histological evaluations, including Nissl staining, immunofluorescence, and immunohistochemistry, revealed that MK886 preserved hippocampal neuron integrity and reduced Aβ deposition. Proteomics and molecular docking analyses identified the PRKCI/AKT signaling pathway as a key mediator of MK886's neuroprotective effects. This finding was further validated through Western blotting experiments incorporating an AKT inhibitor. Overall, these findings suggest that MK886 holds promise as a potential therapeutic agent for Alzheimer's disease by enhancing neuronal protection and cognitive function through the activation of the PRKCI/AKT pathway.

03 Mar 2025·Molecular Pharmaceutics

New PPARα Agonist A190-Loaded Microemulsion for Chemotherapy-Induced Peripheral Neuropathy

Article

Author: Herz, Sara M. ; Berkbigler, Grant ; Duerfeldt, Adam S. ; Pangeni, Rudra ; Poudel, Surendra ; Damaj, M. Imad ; Xu, Qingguo

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect of anticancer agents with limited effective preventive or therapeutic interventions. Although fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPARα) agonist, has demonstrated neuroprotective and analgesic properties, its clinical utility is hindered by low receptor affinity, poor subtype selectivity, and suboptimal bioavailability. A190, a highly selective and potent nonfibrate PPARα agonist, offers a promising alternative but is limited by poor aqueous solubility, resulting in reduced oral bioavailability and therapeutic efficacy. To address these limitations, an optimized oil-in-water (o/w) microemulsion formulation was developed using Box-Behnken design to enhance the solubility and intestinal permeability of A190. The A190 microemulsion exhibited physical stability with a droplet size of approximately 100 nm and a drug loading efficiency of greater than 95%. The effective and apparent permeability of A190 from the microemulsion was significantly higher compared to that of free A190 dispersion, respectively. Additionally, no significant impact on the cell viability was observed, indicating less toxicity and a good biocompatibility of the formulation components. The oral bioavailability of A190 microemulsion was approximately 5-fold higher compared to A190 dispersion, demonstrating the microemulsion's potential to greatly enhance the oral bioavailability of hydrophobic drugs. Furthermore, our findings reveal that orally administered A190 microemulsion effectively reduced CIPN-induced mechanical hypersensitivity, likely mediated through PPARα activation. A190 microemulsion was found to be equally effective at reducing the chronic inflammatory complete Freund's adjuvant-induced pain. These results underscore A190s potential as a nonopioid therapeutic candidate, utilizing a novel microemulsion formulation for the management of chemotherapy-induced neuropathic pain and chronic inflammatory pain.

22 Jan 2025·Journal of Agricultural and Food Chemistry

Sesamol Ameliorates Lipid Deposition by Maintaining the Integrity of the Lipid Droplet–Mitochondria Connection in Diabetic Nephropathy

Article

Author: Liu, Yan ; Zhao, Hao ; Sun, Lin ; Chen, Wei ; Yang, Ming ; Jiang, Na ; Li, Li ; Han, Yachun ; Luo, Shilu ; Liu, Chongbin ; Li, Chenrui ; Xiao, Li

Diabetic nephropathy (DN) is a serious complication of diabetes mellitus and an important cause of end-stage renal disease (ESRD). However, there is still a lack of effective prevention and treatment strategies in clinical practice. As a metabolic disease, DN is accompanied by renal ectopic lipid deposition, and the deposited lipids further aggravate kidney injury. However, the molecular mechanism of renal ectopic lipid deposition is currently unknown. In this study, we observed changes in lipid droplet (LD)-mitochondria connections in the kidney for the first time. Destruction of LD-mitochondria connection was involved in renal lipid deposition in the kidneys of patients and mice with DN or in high-glucose-treated HK-2 cells. Furthermore, sesamol treatment significantly increased the integrity of the LD-mitochondria connection and ameliorated renal lipotoxicity. Finally, we demonstrated that sesamol maintains the integrity of the LD-mitochondria connection by activating the peroxisome proliferator-activated receptor α (PPARα)/perilipin 5 (PLIN5) signaling pathway. Our study is the first to show that the LD-mitochondria connection may be a target for ameliorating lipid deposition in diabetic kidneys.

100 Deals associated with MK-886

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KEGG	Wiki	ATC	Drug Bank
-	MK-886	-	-

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 1	-	Merck Sharp & Dohme Corp.	-
Asthma	Phase 1	United States	Merck GmbH	-
Coronary Thrombosis	Phase 1	United States	Merck GmbH	-
Graft Rejection	Phase 1	United States	Merck GmbH	-
Inflammatory Bowel Diseases	Phase 1	United States	Merck GmbH	-
Inflammatory Bowel Diseases	Phase 1	-	Merck Sharp & Dohme Corp.	-
Neoplasms	Phase 1	United States	Merck GmbH	-
Psoriasis	Phase 1	-	Merck Sharp & Dohme Corp.	-
Psoriasis	Phase 1	United States	Merck GmbH	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ARVO2018	Not Applicable	-	-	Topical fenofibrate	(szkhfdewow) = reduced pljpizkxej (bvhaxdxfam ) View more	-	01 Jul 2018
				Topical fenofibrate plus intraperitoneal injection of MK886

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