Role of F-actin-mediated endocytosis and exercise in mitochondrial transplantation in an experimental Parkinson's disease mouse model.

Dopaminergic neurons gradually deteriorate in Parkinson's Disease (PD), which is characterized by the intracellular accumulation of Lewy bodies that are enriched with α-synuclein protein. Mitochondrial dysfunction is one of the primary contributors to this and is considered as the central player in the pathogenesis of PD. Recently, improving mitochondrial function has been extensively explored as a therapeutic strategy in various preclinical PD models. Mitochondrial transplantation is one such naïve yet highly efficient technique that has been well explored in diseases like diabetes, NAFLD, and cardiac ischemia but not in PD. Here, we compared the effects of transplanting normal allogenic mitochondria to those of transplanting exercise-induced allogenic mitochondria isolated from the liver into the PD mouse model. It is already known that normal Mitochondrial Transplant (MT) reduces the PD pathology, but our research found out that exercise-induced mitochondria were more effective in treating the PD pathology because they had higher respiratory capacities. Additionally, compared to a standard transplant, this therapy significantly boosted the rate of mitochondrial biogenesis and the quantity of mitochondrial subunits in PD mice. Further, we also explored the mechanism of mitochondrial uptake into the cells and found that F-actin plays a key role in the internalization of mitochondria. This study is the first to demonstrate the relevance of exercise-induced allogenic MT and the function of F-actin in the internalization of mitochondria in PD mice.

S1PR2 inhibition mitigates cognitive deficit in diabetic mice by modulating microglial activation via Akt-p53-TIGAR pathway.

Cognitive deficit is one of the challenging complications of type 2 diabetes. Sphingosine 1- phosphate receptors (S1PRs) have been implicated in various neurodegenerative and metabolic disorders. The association of S1PRs and cognition in type 2 diabetes remains elusive. Microglia-mediated neuronal damage could be the thread propagating cognitive deficit. The effects of S1PR2 inhibition on cognition in high-fat diet and streptozotocin-induced diabetic mice were examined in this work. We further assessed microglial activation and putative microglial polarisation routes. Cognitive function loss was observed after four months of diabetes induction in Type 2 diabetes animal model. JTE013, an S1PR2 inhibitor, was used to assess neuroprotection against cognitive decline and neuroinflammation in vitro and in vivo diabetes model. JTE013 (10 mg/kg) improved synaptic plasticity by upregulating psd95 and synaptophysin while reducing cognitive decline and neuroinflammation. It further enhanced anti-inflammatory microglia in the hippocampus and prefrontal cortex (PFC), as evidenced by increased Arg-1, CD206, and YM-1 levels and decreased iNOS, CD16, and MHCII levels. TIGAR, TP53-induced glycolysis and apoptosis regulator, might facilitate the anti-inflammatory microglial phenotype by promoting oxidative phosphorylation and decreasing apoptosis. However, since p53 is a TIGAR suppressor, inhibiting p53 could be beneficial. S1PR2 inhibition increased p-Akt and TIGAR levels and reduced the levels of p53 in the PFC and hippocampus of type 2 diabetic mice, thereby decreasing apoptosis. In vitro, palmitate was used to imitate sphingolipid dysregulation in BV2 cells, followed by conditioned media exposure to Neuro2A cells. JTE013 rescued the palmitate-induced neuronal apoptosis by promoting the anti-inflammatory microglia. In the present study, we demonstrate that the inhibition of S1PR2 improves cognitive function and skews microglia toward anti-inflammatory phenotype in type 2 diabetic mice, thereby promising to be a potential therapy for neuroinflammation.

Fingolimod exerts neuroprotection by regulating S1PR1 mediated BNIP3-PINK1-Parkin dependent mitophagy in rotenone induced mouse model of Parkinson's disease.

The motor impairments brought on by the loss of dopaminergic neurons in the substantia nigra are the most well-known symptoms of Parkinson's disease (PD). It is believed that dopaminergic neurons are especially vulnerable to mitochondrial malfunction. For the maintenance of mitochondrial integrity, selective autophagic removal of dysfunctional mitochondria via mitophagy primarily regulated by PINK1/Parkin pathway is essential. Moreover, newer studies also implicate the role of phospholipid metabolism, such as that of Sphingosine-1-phosphate (S1P) as a contributor to PD. S1P receptors have been reported to influence mitochondrial function in neurodegenerative diseases. Fingolimod (FTY720), an S1P receptor-1 modulator has been proven effective in PD but its regulation of mitophagy in PD is still elusive. In this study, the neuroprotective effect of FTY720 by modulating mitophagy, has been explored against rotenone (ROT) induced neurotoxicity in in-vivo. The animals were randomly divided into 5 groups namely, Normal Control (NC); Disease control (DC): ROT (1.5 mg/kg); Low dose (LD): ROT + FTY720 (0.5 mg/kg); High dose (HD): ROT + FTY720 (1 mg/kg) and Vehicle control (VC): 1 % DMSO. ROT was administered through i.p. and FTY720 through p.o. for 21 days. At the end of the study, various neurobehavioral studies (rotarod test and actimeter), western blot techniques, and immunofluorescence studies were performed. FTY720 restored the neurobehavioural functions and protein expression of PINK1, Parkin and BNIP3 in ROT-induced PD mice. The results obtained in our study suggest that FTY720 has a neuroprotective effect in ROT-induced mice model of PD via PINK1-Parkin mediated mitophagy.

Understanding the involvement of innate immunity and the Nrf2-NLRP3 axis on mitochondrial health in Parkinson's disease.

Parkinson's disease (PD), a multifactorial movement disorder, is interlinked with numerous molecular pathways, including neuroinflammation, which is a critical factor in the development and progression of PD. Microglia play a central role in driving neuroinflammation through activation and overexpression of the M1 phenotype, which has a significant impact on mitochondria. Multiple regulators converge together, and among these, the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes have been implicated in transmitting inflammatory and deleterious components to the mitochondria. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the NLRP3 inflammasome and acts as the saviour of the mitochondria. Together, the NLRP3-Nrf2 axis functions in regulating mitochondrial function in the case of PD. It regulates fundamental processes such as oxidative stress, mitochondrial respiratory function, and mitochondrial dynamics. In this review, we discuss the contributions that a variety of miRNAs make to the regulation of the NLRP3 inflammasome and Nrf2, which can be used to target this important axis and contribute to the preservation of mitochondrial integrity. This axis may prove to be a crucial target for extending the lives of Parkinson's patients by deferring neuroinflammatory damage to mitochondria.

Understanding the Involvement of microRNAs in Mitochondrial Dysfunction and Their Role as Potential Biomarkers and Therapeutic Targets in Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting the elderly worldwide and causing significant movement impairments. The goal of PD treatment is to restore dopamine levels in the striatum and regulate movement symptoms. The lack of specific biomarkers for early diagnosis, as well as medication aimed at addressing the pathogenic mechanisms to decelerate the progression of dopaminergic neurodegeneration, are key roadblocks in the management of PD. Various pathogenic processes have been identified to be involved in the progression of PD, with mitochondrial dysfunction being a major contributor to the disease's pathogenesis. The regulation of mitochondrial functions is influenced by a variety of factors, including epigenetics. microRNAs (miRNAs) are epigenetic modulators involved in the regulation of gene expression and regulate a variety of proteins that essential for proper mitochondrial functioning. They are found to be dysregulated in PD, as evidenced by biological samples from PD patients and in vitro and in vivo research. In this article, we attempt to provide an overview of several miRNAs linked to mitochondrial dysfunction and their potential as diagnostic biomarkers and therapeutic targets in PD.

Alterations in brain white matter microstructural properties in patients with Crohn's disease in remission.

Patients with inflammatory bowel disease have been shown to have abnormal brain morphometry or function, which are associated with psychological symptoms such as stress, depression or anxiety. The present work recruited 20 Crohn's disease patients in remission (CDs) and 20 age-gender-handedness-education matched healthy controls (HCs) and compared their brain white matter microstructural properties using Diffusion Tensor Imaging (DTI). Additionally, we examined the correlations between the microstructural properties and cognition (verbal fluency language task, VF) and affect (anxiety) in both groups as well as disease duration in CDs. Results showed that CDs exhibited significant alterations in microstructural properties compared to HCs in various white matter tracts relevant to language function despite no significant difference in VF scores. Furthermore, CDs' microstructural changes exhibited correlations with anxiety level and disease duration. These findings suggest that CD patients may experience changes in white matter microstructural properties which may be a biomarker of neuropsychiatric comorbidities of CD.

A Verbal Fluency Task-Based Brain Activation fMRI Study in Patients with Crohn's Disease in Remission.

BACKGROUND AND PURPOSE: In this pilot study, we investigated functional brain activation changes in patients with Crohn's disease (CD) in remission compared to age and gender-matched healthy controls (HCs). METHODS: Data from 20 patients with CD in remission (age range 19-63 years) and 20 HCs (matched in age and gender) were analyzed. Task functional MRI (fMRI) data were collected while participants performed a cognitive (phonemic verbal fluency) task in the scanner. All participants also performed the same task outside the scanner. RESULTS: Task fMRI results showed greater bi-hemispheric activation in CD patients compared to controls. Because this pattern is commonly reported with normal aging, we performed further analyses to investigate fMRI responses in a subset of the younger CD patients (N = 12, age < = 35 years) compared to matched young HCs (age < = 35 years), and an older cohort of HCs (age > = 50 years). Results showed that task activation patterns were similar between young CD patients and older HCs, and that both groups differed significantly from younger HCs. Activation intensity in specific brain regions for patients was associated with disease duration. CONCLUSIONS: These results suggest that CD patients in remission may show accelerated signs of aging in terms of brain responses to a typical cognitive task. Future work with larger sample size will need to replicate these results as well as investigate the influence of factors, such as chronicity of the disease and medication effects on task-associated brain activation patterns in this patient population.

Ipsilesional Mu Rhythm Desynchronization and Changes in Motor Behavior Following Post Stroke BCI Intervention for Motor Rehabilitation.

Loss of motor function is a common deficit following stroke insult and often manifests as persistent upper extremity (UE) disability which can affect a survivor's ability to participate in activities of daily living. Recent research suggests the use of brain-computer interface (BCI) devices might improve UE function in stroke survivors at various times since stroke. This randomized crossover-controlled trial examines whether intervention with this BCI device design attenuates the effects of hemiparesis, encourages reorganization of motor related brain signals (EEG measured sensorimotor rhythm desynchronization), and improves movement, as measured by the Action Research Arm Test (ARAT). A sample of 21 stroke survivors, presenting with varied times since stroke and levels of UE impairment, received a maximum of 18-30 h of intervention with a novel electroencephalogram-based BCI-driven functional electrical stimulator (EEG-BCI-FES) device. Driven by spectral power recordings from contralateral EEG electrodes during cued attempted grasping of the hand, the user's input to the EEG-BCI-FES device modulates horizontal movement of a virtual cursor and also facilitates concurrent stimulation of the impaired UE. Outcome measures of function and capacity were assessed at baseline, mid-therapy, and at completion of therapy while EEG was recorded only during intervention sessions. A significant increase in r-squared values [reflecting Mu rhythm (8-12 Hz) desynchronization as the result of attempted movements of the impaired hand] presented post-therapy compared to baseline. These findings suggest that intervention corresponds with greater desynchronization of Mu rhythm in the ipsilesional hemisphere during attempted movements of the impaired hand and this change is related to changes in behavior as a result of the intervention. BCI intervention may be an effective way of addressing the recovery of a stroke impaired UE and studying neuromechanical coupling with motor outputs. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT02098265.

Behavioral Outcomes Following Brain-Computer Interface Intervention for Upper Extremity Rehabilitation in Stroke: A Randomized Controlled Trial.

Stroke is a leading cause of persistent upper extremity (UE) motor disability in adults. Brain-computer interface (BCI) intervention has demonstrated potential as a motor rehabilitation strategy for stroke survivors. This sub-analysis of ongoing clinical trial (NCT02098265) examines rehabilitative efficacy of this BCI design and seeks to identify stroke participant characteristics associated with behavioral improvement. Stroke participants (n = 21) with UE impairment were assessed using Action Research Arm Test (ARAT) and measures of function. Nine participants completed three assessments during the experimental BCI intervention period and at 1-month follow-up. Twelve other participants first completed three assessments over a parallel time-matched control period and then crossed over into the BCI intervention condition 1-month later. Participants who realized positive change (≥1 point) in total ARAT performance of the stroke affected UE between the first and third assessments of the intervention period were dichotomized as "responders" (<1 = "non-responders") and similarly analyzed. Of the 14 participants with room for ARAT improvement, 64% (9/14) showed some positive change at completion and approximately 43% (6/14) of the participants had changes of minimal detectable change (MDC = 3 pts) or minimally clinical important difference (MCID = 5.7 points). Participants with room for improvement in the primary outcome measure made significant mean gains in ARATtotal score at completion (ΔARATtotal = 2, p = 0.028) and 1-month follow-up (ΔARATtotal = 3.4, p = 0.0010), controlling for severity, gender, chronicity, and concordance. Secondary outcome measures, SISmobility, SISadl, SISstrength, and 9HPTaffected, also showed significant improvement over time during intervention. Participants in intervention through follow-up showed a significantly increased improvement rate in SISstrength compared to controls (p = 0.0117), controlling for severity, chronicity, gender, as well as the individual effects of time and intervention type. Participants who best responded to BCI intervention, as evaluated by ARAT score improvement, showed significantly increased outcome values through completion and follow-up for SISmobility (p = 0.0002, p = 0.002) and SISstrength (p = 0.04995, p = 0.0483). These findings may suggest possible secondary outcome measure patterns indicative of increased improvement resulting from this BCI intervention regimen as well as demonstrating primary efficacy of this BCI design for treatment of UE impairment in stroke survivors. Clinical Trial Registration: ClinicalTrials.gov, NCT02098265.