Mitophagy, a Form of Selective Autophagy, Plays an Essential Role in Mitochondrial Dynamics of Parkinson's Disease.

Parkinson's disease (PD) is a severe neurodegenerative disorder caused by the progressive loss of dopaminergic neurons in the substantia nigra and affects millions of people. Currently, mitochondrial dysfunction is considered as a central role in the pathogenesis of both sporadic and familial forms of PD. Mitophagy, a process that selectively targets damaged or redundant mitochondria to the lysosome for elimination via the autophagy devices, is crucial in preserving mitochondrial health. So far, aberrant mitophagy has been observed in the postmortem of PD patients and genetic or toxin-induced models of PD. Except for mitochondrial dysfunction, mitophagy is involved in regulating several other PD-related pathological mechanisms as well, e.g., oxidative stress and calcium imbalance. So far, the mitophagy mechanisms induced by PD-related proteins, PINK1 and Parkin, have been studied widely, and several other PD-associated genes, e.g., DJ-1, LRRK2, and alpha-synuclein, have been discovered to participate in the regulation of mitophagy as well, which further strengthens the link between mitophagy and PD. Thus, in this view, we reviewed mitophagy pathways in belief and discussed the interactions between mitophagy and several PD's pathological mechanisms and how PD-related genes modulate the mitophagy process.

Update on the association between alpha-synuclein and tau with mitochondrial dysfunction: Implications for Parkinson's disease.

The critical role of mitochondrial dysfunction in the pathological mechanisms of neurodegenerative disorders, particularly Parkinson's disease (PD), is well established. Compelling evidence indicates that Parkinson's proteins (e.g., α-synuclein, Parkin, PINK1, DJ-1, and LRRK2) are associated with mitochondrial dysfunction and oxidative stress in PD. Significantly, there is a possible central role of alpha-synuclein (α-Syn) in the occurrence of mitochondrial dysfunction and oxidative stress by the mediation of different signaling pathways. Also, tau, traditionally considered as the main component of neurofibrillary tangles, aggregates and amplifies the neurotoxic effects on mitochondria by interacting with α-Syn. Moreover, oxidative stress caused by mitochondrial dysfunction favors assembly of both α-Syn and tau and also plays a key role in the formation of protein aggregates. In this review, we provide an overview of the relationship between these two pathological proteins and mitochondrial dysfunction in PD, and also summarize the underlying mechanisms in the interplay of α-Syn aggregation and phosphorylated tau targeting the mitochondria, to find new strategies to prevent PD processing.

Parkin, an E3 Ubiquitin Ligase, Plays an Essential Role in Mitochondrial Quality Control in Parkinson's Disease.

Parkinson's disease (PD), as one of the complex neurodegenerative disorders, affects millions of aged people. Although the precise pathogenesis remains mostly unknown, a significant number of studies have demonstrated that mitochondrial dysfunction acts as a major role in the pathogeny of PD. Both nuclear and mitochondrial DNA mutations can damage mitochondrial integrity. Especially, mutations in several genes that PD-linked have a closed association with mitochondrial dysfunction (e.g., Parkin, PINK1, DJ-1, alpha-synuclein, and LRRK2). Parkin, whose mutation causes autosomal-recessive juvenile parkinsonism, plays an essential role in mitochondrial quality control of mitochondrial biogenesis, mitochondrial dynamics, and mitophagy. Therefore, we summarized the advanced studies of Parkin's role in mitochondrial quality control and hoped it could be studied further as a therapeutic target for PD.

Role of mitophagy in mitochondrial quality control: Mechanisms and potential implications for neurodegenerative diseases.

Neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis) commonly characterized by the gradual loss of neurons have a seriously bad impact on motor and cognitive abilities of affected humans and bring great inconvenience to their lives. Mitochondrial dysfunction has been considered the key and common factor for the pathologies of neurodegenerative diseases for that neurons are extremely energy-intensive due to their unique properties in structures and functions. Thus, mitophagy, as a central role of mitochondrial quality control and currently believed to be the most effective pathway to clear dysfunctional or unwanted mitochondria, is rather crucial in the preservation of neuronal health. In addition, mitophagy establishes an intimated link with several other pathways of mitochondrial quality control (e.g., mitochondrial biogenesis and mitochondrial dynamics), and they work together to preserve mitochondrial health. Therefore, in this review, we summarized the recent process on the mechanisms of mitophagy pathways in mammals, it's linking to mitochondrial quality control, its role in several major neurodegenerative diseases, and possible therapeutic interventions focusing on mitophagy pathways. And we expect that it can provide us with more understanding of the mitophagy pathways and more promising approaches for the treatment of neurodegenerative diseases.

Novel rapid-acting glutamatergic modulators: Targeting the synaptic plasticity in depression.

Major depressive disorder (MDD) is severely prevalent, and conventional monoaminergic antidepressants gradually exhibit low therapeutic efficiency, especially for patients with treatment-resistant depression. A neuroplasticity hypothesis is an emerging advancement in the mechanism of depression, mainly expressed in the glutamate system, e.g., glutamate receptors and signaling. Dysfunctional glutamatergic neurotransmission is currently considered to be closely associated with the pathophysiology of MDD. Biological function, pharmacological action, and signal attributes in the glutamate system both regulate the neural process. Specific functional subunits could be therapeutic targets to explore the novel glutamatergic modulators, which have fast-acting, and relatively sustained antidepressant effects. Here, the present review summarizes the pathophysiology of MDD found in the glutamate system, exploring the role of glutamate receptors and their downstream effects. These convergent mechanisms have prompted the development of other modulators targeting on glutamate system, including N-methyl-d-aspartate receptor antagonists, selective GluN2B-specific antagonists, glycine binding site agents, and regulators of metabotropic glutamate receptors. Relevant researches underly the putative mechanisms of these drugs, which reverse the damage of depression by regulating glutamatergic neurotransmission. It also provides further insight into the mechanism of depression and exploring potential targets for novel agent development.

Dynamin-related protein 1: A protein critical for mitochondrial fission, mitophagy, and neuronal death in Parkinson's disease.

Parkinson's disease (PD) that afflicts millions of individuals worldwide is associated with deposits of aggregate-prone proteins (e.g., α-synuclein) and with mitochondrial dysfunction in neuronal cells. Mitochondria are the main source of reactive oxygen species, provide energy for neuronal cells, and are regarded as dynamic organelles that are determined by mitochondrial fission, fusion, and mitophagy to maintain mitochondrial homeostasis. Growing evidence reveals that several dynamics-related proteins, such as dynamin-related protein 1 (Drp1), mediate mitochondrial fission, fusion, and mitophagy, to protect against neurodegeneration in PD. More importantly, not only is Drp1-mediated fission required for mitophagy that exerts a protective effect on neurons, but abnormal mitochondrial fission and mitophagy can drive neuronal survival or cell death (i.e., autophagy, apoptosis, and necroptosis), suggesting that Drp1 may play a pivotal role in the pathogenesis of PD. Also, PD-related proteins such as α-synuclein, leucine-rich repeat kinase-2, PTEN-induced putative kinase 1, and Parkin have been proven to interact with Drp1, thus contributing to mitochondrial dynamics and clearance, as well as neuronal fate. Here, we review the roles of Drp1 in mitochondrial fission, dynamics, mitophagy, bulk autophagy, apoptosis, and necroptosis for a better understanding of mitochondrial disturbances in PD-associated neurodegeneration and summarize the advances of novel chemical compounds targeting Drp1 to provide new insight into potential PD therapies.

Mangiferin: A multipotent natural product preventing neurodegeneration in Alzheimer's and Parkinson's disease models.

Alzheimer's disease (AD) and Parkinson's disease (PD) are recognized as the universal neurodegenerative diseases, with the involvement of misfolded proteins pathology, leading to oxidative stress, glial cells activation, neuroinflammation, mitochondrial dysfunction, and cellular apoptosis. Several discoveries indicate that accumulation of pathogenic proteins, i.e. amyloid ß (Aß), the microtubule-binding protein tau, and α-synuclein, are parallel with oxidative stress, neuroinflammation, and mitochondrial dysfunction. Whether the causative factors are misfolded proteins or these pathophysiological changes, leading to neurodegeneration still remain ambiguous. Importantly, directing pharmacological researches towards the prevention of AD and PD seem a promising approach to detect these complicating mechanisms, and provide new insight into therapy for AD and PD patients. Mangiferin (MGF, 2-C-ß-D-glucopyranosyl-1, 3, 6, 7-tetrahydroxyxanthone), well-known as a natural product, is detached from multiple plants, including Mangifera indica L. With the structure of C-glycosyl and phenolic moiety, MGF possesses multipotent properties starting from anti-oxidant effects, to the alleviation of mitochondrial dysfunction, neuroinflammation, and cellular apoptosis. In particular, MGF can cross the blood-brain barrier to exert neuronal protection. Different researches implicate that MGF is able to protect the central nervous system from oxidative stress, mitochondrial dysfunction, neuroinflammation, and apoptosis under in vitro and in vivo models. Additional facts support that MGF plays a role in improving the declined memory and cognition of rat models. Taken together, the neuroprotective capacity of MGF may stand out as an agent candidate for AD and PD therapy.

Efficacy and safety of istradefylline for Parkinson's disease: A systematic review and meta-analysis.

As an adenosine receptor A2A antagonist, istradefylline is used as an adjunctive agent of levodopa to improve motor symptoms in advanced Parkinson's disease (PD) patients. In this study, we re-evaluated the effects of istradefylline on treating the motor symptoms of PD patients. We performed a literature search up to November 2021 from electronic databases. Eligible studies were synthesized for efficacy, tolerability, OFF time, Unified Parkinson's Disease Rating Scale part III score, ON state with dyskinesia, and the incidence of treatment-emergent adverse events. As a result, nine clinical studies with 2727 subjects on istradefylline treatment for PD patients were included. Our results showed that compared to placebo, istradefylline exhibited a statically significant difference in efficacy (1.39 [1.15 to 1.69]; p = 0.001), decreasing OFF time (-0.58 [-1.01 to - 0.16]; p = 0.007), and improving ON state with dyskinesia (0.69 [0.02 to 1.37]; p = 0.043). For tolerability, UPDRS III, and adverse effects, there was no significant difference between istradefylline and placebo. In conclusion, the results suggest that istradefylline exhibits an efficient and well-tolerated role in treating PD patients. Randomized controlled trials and long-term studies are still required to investigate the effects of istradefylline on motor and non-motor symptoms of PD in future research.

Comparative efficacy and acceptability of drug treatments for Parkinson's disease with depression: A systematic review with network meta-analysis.

Depressive symptom is the prevailing non-motor symptom of Parkinson's disease (PD). Drug treatments for depressed PD (dPD) can mitigate the symptoms of patients. However, the results are discordant and need further analysis. This systematic review with network meta-analysis aims to evaluate the drug treatments for dPD. We included double-blind, randomized controlled trials to compare antidepressants with placebo or other antidepressants in dPD. We performed traditional pairwise analysis and network meta-analysis concerning the efficacy, acceptability, depression score, and adverse effect. The surface under the cumulative ranking curve was to assess the ranking probabilities of the enrolled agents. We enrolled 62 studies, including 12,353 subjects, to analyze these estimates. For the traditional pairwise meta-analysis, dopamine agonist (DOP; OR = 2.20 [95% CI, 1.46 to 3.33]) and selective serotonin reuptake inhibitor (SSRI; OR = 2.30 [95% CI, 1.15 to 4.60]) were observed to improve the efficacy compared with placebo. For network meta-analysis, DOP was observed to improve the efficacy compared with placebo (OR = -0.84 [95% CI, -1.20 to -0.48]). Both direct and indirect evidence showed that several treatments, e.g., DOP, monoamine-oxidase inhibitor, serotonin-norepinephrine reuptake inhibitors, SSRI, and tricyclic antidepressants, significantly improved depressive symptoms. DOP and SSRI had good efficacy and improved symptoms considerably in dPD, but the adverse effect of these agents was needed to follow closely.

Canonical Chinese medicine formula Danzhi-Xiaoyao-San for treating depression: A systematic review and meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Danzhi-Xiaoyao-San (DXS), as a canonical Chinese medicine formula, possessing the functions of the soothing liver, invigorating spleen, clearing heat, and cooling blood, has been widely used for the treatment of depression. AIM OF THE STUDY: This systematic review and meta-analysis of randomized controlled trials aimed to examine the efficacy of DXS in depression. MATERIALS AND METHODS: We performed a literature search in several databases, e.g., PUBMED, until August 2021 and conducted the meta-analysis using Review Manager 5.3 software. The random-effects model and fixed-effects model were used to synthetize extracted data. RESULTS: Finally, this meta-analysis showed that comparing with antidepressants, DXS exhibited similar effect to antidepressants in the clinical comprehensive effect [RR = 1.04, 95% CI (0.77, 1.40); P = 0.81] and decrease in Self-Rating Depression Scale scores [WMD = 0.89, 95% CI (-6.33, 8.11); P = 0.81], while lower effect in Hamilton Depression Scale scores [SMD = -0.29, 95% CI (-0.55, -0.03); P = 0.03]; Furthermore, DXS plus antidepressants can significantly improve the clinical comprehensive effect [RR = 1.23, 95% CI (1.17, 1.29); P < 0.00001] and decrease the Hamilton Depression Scale scores [SMD = 1.04, 95% CI (0.51, 1.58); P = 0.0001] than pure antidepressants. CONCLUSION: This systematic review and meta-analysis approved an efficient role of DXS in improving depression in clinical randomized controlled trials. However, further evidence from large samples and high-quality randomized controlled trials is needed to be investigated for a reliable conclusion about DXS in the treatment of depression.

Mangiferin, a natural glucoxilxanthone, inhibits mitochondrial dynamin-related protein 1 and relieves aberrant mitophagic proteins in mice model of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease featured to mitochondrial dysfunction in neuronal cells. Dynamin-related protein 1 (Drp1) is an important regulator of mitochondrial fission and subsequent mitophagy. Mangiferin (MGF) is a glucosyl xanthone mainly derived from Mangifera indica L., possessing multifaceted properties, e.g., antioxidant, anti-inflammatory, and enhancement of cognitive ability. Besides, it can cross the blood-brain barrier, thereby exerting a neuroprotective effect. However, so far, MGF's effect in balancing mitochondrial homeostasis via regulation of Drp1 level and mitophagic pathway in PD remains rarely reported. PURPOSE: We aimed to investigate the neuroprotective effect of MGF against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD and examine the possible mechanisms. METHODS: We utilized C57BL/6 mice exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); Behavioral parameters, containing the open field test, balance beam, pole test, and rotarod test, assessed the locomotor activity; immunohistochemistry assessed the number of TH-positive neurons; transmission electron microscopy detected ultrastructural mitochondrial morphology in the dopaminergic neuron; complex I enzymatic activity microplate assay kit measured the mitochondrial complex I activity; ATP determination kit measured ATP levels in mitochondria isolated from cells or striatal tissues; western blot measured the levels of Drp1 and mitophagic proteins. RESULTS: We observed that MGF could mitigate motor deficiency and improve the expression of tyrosine hydroxylase in the substantia nigra of MPTP-induced PD mice. Furthermore, MGF not only ameliorated mitochondrial ultrastructure, but also improved mitochondrial ATP content. Within mitochondria, MGF could reduce Drp1 expression and reverse the expressions of mitophagic proteins, including PINK1, Parkin, NIX, BNIP3, FUNDC1, and p62. CONCLUSION: Present study indicates that MGF benefits mitochondrial networks by recovering mitochondrial ultrastructure and ATP contents, reducing mitochondrial Drp1, and modulating mitophagic proteins in the MPTP-induced PD mice model, which revealed a novel acting mechanism of MGF in PD's treatment.

Paeoniflorin: A neuroprotective monoterpenoid glycoside with promising anti-depressive properties.

BACKGROUND: Depression, as a prevalent and debilitating psychiatric disease, severely decreases the life quality of individuals and brings heavy burdens to the whole society. Currently, some antidepressants are applied in the treatment of severe depressive symptoms, while there are still some undesirable drawbacks. Paeoniflorin is a monoterpenoid glycoside that was firstly extracted from Paeonia lactiflora Pall, a traditional Chinese herb that is widely used in the Chinese herbal formulas for treating depression. PURPOSE: This review summarized the previous pre-clinical studies of paeoniflorin in treating depression and further discussed the potential anti-depressive mechanisms for that paeoniflorin to be further explored and utilized in the treatment of depression clinically. METHODS: Some electronic databases, e.g., PubMed and China National Knowledge Infrastructure, were searched from inception until April 2021. RESULTS: This review summarized the effective anti-depressive properties of paeoniflorin, which is related to its functions in the upregulation of the levels of monoaminergic neurotransmitters, inhibition of the hypothalamic-pituitary-adrenal axis hyperfunction, promotion of neuroprotection, promotion of hippocampus neurogenesis, and upregulation of brain-derived neurotrophic factor level, inhibition of inflammatory reaction, downregulation of nitric oxide level, etc. CONCLUSION: This review focused on the pre-clinical studies of paeoniflorin in depression and summarized the recent development of the anti-depressive mechanisms of paeoniflorin, which approves the role of paeoniflorin plays in anti-depression. However, more high-quality pre-clinical and clinical studies are expected to be conducted in the future.

Inhibition of dynamin-related protein 1 ameliorates the mitochondrial ultrastructure via PINK1 and Parkin in the mice model of Parkinson's disease.

Parkinson's disease (PD) is the prevalent neurodegenerative disorder characterized by the degeneration of the nigrostriatal neurons. Dynamin-related protein 1 (Drp1) is a key regulator mediating mitochondrial fission and affecting mitophagy in neurons. It has been reported that the inhibition of Drp1 may be beneficial to PD. However, the role of Drp1 and mitophagy in PD remains elusive. Therefore, in this research, we investigated the role of Drp1 and the underlying mechanisms in the mice model of PD. We used the dynasore, a GTPase inhibitor, to inhibit the expression of Drp1. We found that inhibition of Drp1 could ameliorate the motor deficits and the expression of tyrosine hydroxylase in the mice of the PD model. But Drp1 inhibition did not affect mitochondria number and morphological parameters. Moreover, suppression of Drp1 up-regulated the mitochondrial expressions of PINK1 and Parkin while not affected the expressions of NIX and BNIP3. Conclusively, our findings suggest that the inhibition of Drp1 ameliorated the mitochondrial ultrastructure at least via regulating PINK1 and Parkin in the mice of the PD model. This study also implicates that inhibition of Drp1 might impact mitophagy and recover mitochondrial homeostasis in PD.

Efficacy of Traditional Chinese Medicine Combined with Selective Serotonin Reuptake Inhibitors on the Treatment for Parkinson's Disease with Depression: A Systematic Review and Meta-Analysis.

Depression is a common neuropsychiatric symptom of Parkinson's disease (PD), resulting in a lower quality of life and cognitive impairment in PD patients. Traditional Chinese medicine (TCM) formulas have been widely used in neurodegenerative disease and neuropsychic disorders to improve life quality of patients in ethnomedicine. TCM formulas combined with selective serotonin reuptake inhibitors (SSRIs) also have a positive effect on depressed PD compared with SSRIs as reported by several clinical studies. However, the results are discordant and failed to be conclusive. We aim to evaluate the efficacy of TCM formulas combined with SSRIs for depressed PD in this systematic review. We searched literatures from PubMed, Web of Science, Medline, Embase, Google Scholar, Chinese National Knowledge Infrastructure, Wanfang Database, and VIP Information Database before July 2020. We included randomized controlled trials investigating the efficacy of TCM formulas combined with SSRIs on depressed PD patients. This analysis was according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. Eleven randomized clinical trials involving 861 subjects were enrolled in this analysis. The overall results showed that TCM formulas combined with SSRIs significantly improved the depression score [weighted mean difference (WMD): -4.920, 95% confidence interval (CI): (-5.999, -3.840); [Formula: see text]¡ 0.001] and had a statistical significance on Unified Parkinson's Disease Rating Scale II score [WMD: -1.209, 95% CI: (-1.561, -0.857); [Formula: see text] < 0.001]. Furthermore, we observed that Chai-Hu-Shu-Gan Powder combined with SSRIs had a significant improvement on the depressive symptom in PD compared to the SSRIs alone [WMD: -5.390, 95% CI: (-7.66, -3.11); [Formula: see text] < 0.001]. No severe side events were reported in these included trials. This systematic review provided the evidences that TCM formulas combined with SSRIs might be helpful and safe in the treatment of depression of PD, including Chai-Hu-Shu-Gan Powder. Also, more randomized double-blinded trials with reliable design are required in the future.

Connexin 43: A novel ginsenoside Rg1-sensitive target in a rat model of depression.

Our previous studies have shown that ginsenoside Rg1 (Rg1) exerts antidepressant-like effects in animal models of depression, accompanied by an improvement of astrocytic gap junction functions. However, whether connexin 43 (Cx43), the major connexin forming gap junctions between astrocytes, is the key regulator of Rg1-induced antidepressant-like effects is still unknown. In this study, we examine in vitro and in vivo the involvement of Cx43 in the antidepressant effects of Rg1. Corticosterone was used to establish an in vitro rat model of depression. Treatment with Rg1 1 h prior to corticosterone significantly improved the cell viability of astrocytes, which was significantly inhibited by carbenoxolone, a widely used gap junction inhibitor. Moreover, Rg1 treatment significantly ameliorated antidepressant-sensitive behaviours induced by infusion of carbenoxolone or Gap26, a selective inhibitor of Cx43, into the prefrontal cortex of the animals. Rg1 treatment increased the expression of Cx43 compared with Gap26 group. According to these results, the antidepressant-like effects of Rg1 were mainly mediated by Cx43-formed gap junctions.