Neuroinflammation, oxidative stress, and mitochondrial dysfunction are all important pathogenic mechanisms underlying motor dysfunction and dopaminergic neuronal damage observed in patients with Parkinson’s disease (PD). However, despite extensive efforts, targeting inflammation and oxidative stress using various approaches has not led to meaningful clinical outcomes, and mitochondrial enhancers have also failed to convincingly achieve disease-modifying effects. We tested our hypothesis that treatment approaches in PD should simultaneously reduce neuroinflammation, oxidative stress, and improve alterations in neuronal energy metabolism using the flavonoid icaritin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Using matrix-assisted laser desorption/ionization–mass spectrometry imaging (MALDI-MSI), coupled with biochemical analyses and behavioral tests, we demonstrate that icaritin improves PD by attenuating the the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome activity and stabilizing mitochondrial function, based on our extensive analyses showing the inhibition of NLRP3 inflammasome, reduction of NLRP3-mediated IL-1β secretion, and improvements in the levels of antioxidant molecules. Our data also indicated that icaritin stabilized the levels of proteins related to mitochondrial function, such as voltage-dependent anion channel (VDAC) and ATP synthase subunit beta (ATP5B), as well as those of molecules related to energy metabolism, such as ATP and ADP, ultimately improving mitochondrial dysfunction. By employing molecular docking, we also discovered that icaritin can interact with NLRP3, VDAC, ATP5B, and several blood–brain barrier (BBB)-related proteins. These data provide insights into the promising therapeutic potential of icaritin in PD.

Radix Aconiti Lateralis Preparata (fuzi) is the processed product of Aconitum carmichaelii Debeaux tuber, and has great potential anti-myocardial infarction effects, including improving myocardial damage and energy metabolism in rats. However, the effects of Radix Aconiti Lateralis Preparata extracts in a rat model of myocardial infarction have not yet been fully illustrated. Herein, Radix Aconiti Lateral Preparata was used to prepare Radix Aconiti Lateralis Preparata extract (RAE), fuzi polysaccharides (FPS), and fuzi total alkaloid (FTA). Then, we aimed to compare the effects of RAE, FPS, and FTA in MI rats and further explore their influence on small molecules in the heart. We reported that Radix Aconiti Lateralis Preparata extract (RAE) and fuzi total alkaloid (FTA) significantly improved left ventricular function and structure, and reduced myocardial damage and infarct size in rats with myocardial infarction by the left anterior descending artery ligation. In contrast, fuzi polysaccharides (FPS) was less effective than RAE and FTA, indicating that alkaloids might play a major role in the treatment of myocardial infarction. Moreover, via matrix-assisted laser desorption/ionization–mass spectrometry imaging (MALDI–MSI), we further showed that RAE and FTA containing alkaloids as the main common components regulated myocardial energy metabolism-related molecules and phospholipids levels and distribution patterns against myocardial infarction. In particular, it was FTA, not RAE, that could also regulate potassium ions and glutamine to play a cardioprotective role in myocardial infarction, which revealed that an appropriate dose of alkaloids generated more obvious cardiotonic effects. These findings together suggested that Radix Aconiti Lateralis Preparata extracts containing an appropriate dose of alkaloids as its main pharmacological active components exerted protective effects against myocardial infarction by improving myocardial energy metabolism abnormalities and changing phospholipids levels and distribution patterns to stabilize the cardiomyocyte membrane structure. Thus, RAE and FTA extracted from Radix Aconiti Lateralis Preparata are potential candidates for the treatment of myocardial infarction.

Degeneration and death of dopaminergic neurons in the substantia nigra of the midbrain are the main pathological changes in Parkinson’s disease (PD); however, the mechanism underlying the selective vulnerability of specific neuronal populations in PD remains unclear. Here, we used single-cell RNA sequencing to identify seven cell clusters, including oligodendrocytes, neurons, astrocytes, oligodendrocyte progenitor cells, microglia, synapse-rich cells (SRCs), and endothelial cells, in the substantia nigra of a rotenone-induced rat model of PD based on marker genes and functional definitions. We found that SRCs were a previously unidentified cell subtype, and the tight interactions between SRCs and other cell populations can be improved by icaritin, which is a flavonoid extracted from Epimedium sagittatum Maxim. and exerts anti-neuroinflammatory, antioxidant, and immune-improving effects in PD. We also demonstrated that icaritin bound with transcription factors of SRCs, and icaritin application modulated synaptic characterization of SRCs, neuroinflammation, oxidative stress, and survival of dopaminergic neurons, and improved abnormal energy metabolism, amino acid metabolism, and phospholipase D metabolism of astrocytes in the substantia nigra of rats with PD. Moreover, icaritin supplementation also promotes the recovery of the physiological homeostasis of the other cell clusters to delay the pathogenesis of PD. These data uncovered previously unknown cellular diversity in a rat model of Parkinson’s disease and provide insights into the promising therapeutic potential of icaritin in PD.