Diosgenin derivative ML5 attenuates MPTP-induced neuronal impairment via regulating AMPK/PGC-1α-mediated mitochondrial biogenesis and fusion/fission.

OBJECTIVE: The aim of the present study was to assess the therapeutic impact of diosgenin derivative ML5 on Parkinson's disease (PD) and explore the mechanism underlying mitochondrial biogenesis and fusion/fission. METHODS: We established 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse models and N-methyl-4-phenylpyridinium iodide (MPP+)-induced cell models of PD. The pole test and forced swimming test were used to detect the motor coordination and depressive symptoms in mice. The influence of ML5 on dopaminergic neuronal injury was investigated. Meanwhile, adenosine triphosphate (ATP) content, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) production were measured to evaluate mitochondrial function. Confocal and transmission electron microscopy were used to detect mitochondrial morphology of cell. The expression of mitochondrial biogenesis-related proteins was measured by Western blotting. RESULTS: The administration of ML5 showed the neuroprotection against MPTP-induced damage in vivo and in vitro. The levels of ATP, MMP, and ROS were restored after ML5 administration. In addition, we observed that ML5 preserved the mitochondrial network morphology and inhibited mitochondrial fission. Furthermore, the amelioration of mitochondrial dysfunction was mediated by enhancing 5'-monophosphate-activated protein kinase (AMPK) and peroxisome proliferators-activated receptor γ coactivator-l alpha (PGC-1α) expression, which activated its downstream modulators leading to the enhancing of mitochondrial biogenesis and the balance of mitochondrial fusion/fission. CONCLUSION: ML5 can protect the PD models against MPTP/MPP+-induced mitochondrial dysfunction and neuronal injury via promoting AMPK/PGC-1α signaling activation and be used as a therapeutic drug for PD treatment.

Design, synthesis, and biological evaluation of diosgenin-indole derivatives as dual-functional agents for the treatment of Alzheimer's disease.

The complex pathogenesis of Alzheimer's disease (AD) has become a major obstacle in its treatment. An effective approach is to develop multifunctional agents that simultaneously target multiple pathological processes. Here, a series of diosgenin-indole compounds were designed, synthesized and evaluated for their neuroprotective effects against H2O2 (hydrogen peroxide), 6-OHDA (6-hydroxydopamine) and Aß (beta amyloid) damages. Preliminary structure-activities relationship revealed that the introduction of indole fragment and electron-donating group at C-5 on ring indole could be beneficial for neuroprotective activities. Results indicated that compound 5b was the most promising candidate against cellular damage induced by H2O2 (52.9 ± 1.9%), 6-OHDA (38.4 ± 2.4%) and Aß1-42 (54.4 ± 2.7%). Molecular docking study suggested the affinity for 5b bound to Aß1-42 was -40.59 kcal/mol, which revealed the strong binding affinity of 5b to Aß1-42. The predicted values of brain/blood partition coefficient (-0.733) and polar surface area (85.118 Å2) indicated the favorable abilities of BBB permeation and absorption of 5b. In addition, 5b significantly decreased ROS (reactive oxygen species) production induced by H2O2. In the following in vivo experiment, 5b obviously attenuated memory and learning impairments of Aß-injected mice. In summary, compound 5b could be considered as a promising dual-functional neuroprotective agent against AD.

The immunosuppressant fingolimod ameliorates experimental autoimmune myasthenia gravis by regulating T-cell balance and cytokine secretion.

Myasthenia gravis is an autoimmune disease that affects skeletal muscle strength by impeding communication within the neuromuscular junction (NMJ). Research has shown that sphingosine-1-phosphate (S1P)/S1P receptor signaling may be involved in the process of neuromuscular diseases. Fingolimod is structurally similar to S1P, whose immunosuppressive effect has been recognized in many immune diseases. However, the mechanism underlying fingolimod's action on experimental autoimmune myasthenia gravis is still far from clear. The aim of this study was to investigate the efficacy and possible mechanism of fingolimod on experimental autoimmune myasthenia gravis. Our results showed that pretreatment with fingolimod improved experimental autoimmune myasthenia gravis symptoms in a dose-dependent manner, including decreased anti-acetylcholine receptor-2α autoantibody titer, reduced compound muscle action potential decrement, and increased acetylcholine receptor content. Further investigation indicated that fingolimod inhibited lymphocyte proliferation responses and also regulated the balance of Th1/Th2 cells and Treg/Th17 cells. Moreover, fingolimod suppressed the secretion of pro-inflammatory or inflammatory cytokines IL-17A, IL-6, and INF-γ, but did not noticeably alter the secretion of immunosuppressive cytokines TGF-ß1 and IL-4. In conclusion, our results suggest that fingolimod has a preventive effect on experimental autoimmune myasthenia gravis by interfering with lymphocyte function.