Trial of Lixisenatide in Early Parkinson's Disease.

BACKGROUND: Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson's disease. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson's disease. Participants in whom Parkinson's disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent. RESULTS: A total of 156 persons were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by -0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P = 0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%. CONCLUSIONS: In participants with early Parkinson's disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson's disease. (Funded by the French Ministry of Health and others; LIXIPARK ClinicalTrials.gov number, NCT03439943.).

Neuroprotective role of FOXA1 in Parkinson's disease: Involvements of NF1 transcription activation and MAPK signaling pathway inhibition.

Forkhead box A1 (FOXA1), a member of the forkhead family of transcription factors, plays a crucial role in the development of various organ systems and exhibits neuroprotective properties. This study aims to investigate the effect of FOXA1 on Parkinson's disease (PD) and unravel the underlying mechanism. Transcriptome analysis of PD was conducted using three GEO datasets to identify aberrantly expressed genes. A mouse model of PD was generated by injecting neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP), resulting in reduced FOXA1 expression. FOXA1 decline was also observed in 1-methyl-4-phenylpyridinium-treated SH-SY5Y cells. Artificial upregulation of FOXA1 improved motor abilities of mice according to rotarod and pole tests, and it mitigated tissue damage, cell loss, and neuronal damage in the mouse substantia nigra or in vitro. FOXA1 was found to bind to the neurofibromin 1 (NF1) promoter, thereby inducing its transcription and inactivating the mitogen-activated protein kinase (MAPK) signaling pathway. Further experimentation revealed that silencing NF1 in mice or SH-SY5Y cells counteracted the neuroprotective effects of FOXA1. In conclusion, this research suggests that FOXA1 activates NF1 transcription and inactivates the MAPK signaling pathway, ultimately ameliorating neuronal damage and motor disability in PD. The findings may offer novel ideas in the field of PD management.

Effects of Amantadine Sulfate on Motor Impairment and Execution of Motor Sequences in Patients With Parkinson Disease.

BACKGROUND: Intravenous application of amantadine sulfate induces a rapid improvement of motor behavior in patients with Parkinson disease. OBJECTIVES: To determine efficacy of daily infusion of 200 mg amantadine sulfate on scored motor symptoms and performance of standardized movement sequences with components of low and high cognitive efforts. METHODS: Thirty-one participants received infusions of amantadine sulfate in addition to their previous stable drug regimens on 3 consecutive days. Motor symptoms of upper limbs were determined with selected items of the part motor examination of the Unified Parkinson's Disease Rating Scale. Instrumental tasks were executed under cued conditions before and after the infusions. RESULTS: Scored motor symptoms and components with a need for a higher cognitive load became better. Performance of motion series, characterized by an automated set with low cognitive efforts, did not improve. CONCLUSION: Our trial outcomes suggest that the amantadine has a positive impact on cognitive abilities, drive, and vigilance, all of which are necessary for carrying out of higher brain functions.

Anti-parkinsonian activity of the adenosine A2A receptor antagonist/inverse agonist KW-6356 as monotherapy in MPTP-treated common marmosets.

KW-6356 is a novel adenosine A2A receptor antagonist/inverse agonist that not only blocks binding of adenosine to adenosine A2A receptor but also inhibits the constitutive activity of adenosine A2A receptor. The efficacy of KW-6356 as both monotherapy and an adjunct therapy to L-3,4-dihydroxyphenylalanine (L-DOPA)/decarboxylase inhibitor in Parkinson's disease (PD) patients has been reported. However, the first-generation A2A antagonist istradefylline, which is approved for use as an adjunct treatment to L-DOPA/decarboxylase inhibitor in adult PD patients experiencing OFF episodes, has not shown statistically significant efficacy as monotherapy. In vitro pharmacological studies have shown that the pharmacological properties of KW-6356 and istradefylline at adenosine A2A receptor are markedly different. However, the anti-parkinsonian activity and effects on dyskinesia of KW-6356 in PD animal models and the differences in the efficacy between KW-6356 and istradefylline are unknown. The present study investigated the anti-parkinsonian activity of KW-6356 as monotherapy in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets, and its efficacy was directly compared with that of istradefylline. In addition, we investigated whether or not repeated administration of KW-6356 induced dyskinesia. Oral administration of KW-6356 reversed motor disability in a dose-dependent manner up to 1 mg/kg in MPTP-treated common marmosets. The magnitude of anti-parkinsonian activity induced by KW-6356 was significantly greater than that of istradefylline. Repeated administration of KW-6356 induced little dyskinesia in MPTP-treated common marmosets primed to exhibit dyskinesia by prior exposure to L-DOPA. These results indicate that KW-6356 can be a novel non-dopaminergic therapy as monotherapy without inducing dyskinesia in PD patients.

Botulinum Toxin Treatment of Motor Disorders in Parkinson Disease-A Systematic Review.

This review provides an up-to-date literature account on the efficacy of Botulinum toxin treatment for common motor disorders of Parkinson Disease. The reviewed disorders include the common motor disorders in PD such as tremor, focal foot dystonia, rigidity and freezing of gait (FOG). In the area of Parkinson tremor, two newly described evaluation/injection techniques (Yale method in USA and Western University method in Canada) offer efficacy with low incidence of hand and finger weakness as side effects. Blinded studies conducted on foot dystonia of PD indicate that botulinum toxin injections into toe flexors are efficacious in alleviating this form of dystonia. Small, blinded studies suggest improvement of Parkinson rigidity after botulinum toxin injection; proof of this claim, however, requires information from larger, blinded clinical trials. In FOG, the improvement reported in open label studies could not be substantiated in blinded investigations. However, there is room for further controlled studies that include the proximal lower limb muscles in the injection plan and/or use higher doses of the injected toxin for this indication.

Neuroprotective effects of bornyl acetate on experimental autoimmune encephalomyelitis via anti-inflammatory effects and maintaining blood-brain-barrier integrity.

BACKGROUND: Bornyl acetate (BA), a chemical component of essential oil in the Pinus family, has yet to be actively studies in terms of its therapeutic effect on numerous diseases, including autoimmune diseases. PURPOSE: This study aimed to investigate the pharmacological effects and molecular mechanisms of BA on myelin oligodendrocyte glycoprotein (MOG35-55)-induced experimental autoimmune encephalomyelitis (EAE) mice in an animal model of multiple sclerosis (MS), a representative autoimmune disease in central nervous system. METHODS: BA (100, 200, or 400 mg/kg) was orally treated to EAE mice once daily for 30 days after immunization for the behavioral test and for the 16th-18th days for the histopathological and molecular analyses, from the onset stage (8th day) of EAE symptoms. RESULTS: BA mitigated behavioral dysfunction (motor disability) and demyelination in the spinal cord that were associated with the down-regulation of representative pro-inflammatory cytokines (interleukin (IL)-1 beta, IL-6, and tumor necrosis factor-alpha), enzymes (cyclooxygenase-2 and inducible nitric oxide synthase), and chemokines (monocyte chemotactic protein-1, macrophage inflammatory protein-1 alpha, and regulated on activation), and decreased infiltration of microglia (CD11b+/CD45+(low)) and macrophages (CD11b+/CD45+(high)). The anti-inflammatory effect of BA was related to the inhibition of mitogen-activated protein kinases and nuclear factor-kappa B pathways. BA also reduced the recruitment/infiltration rates of CD4+ T, Th1, and Th17 cells into the spinal cords of EAE mice, which was related to reduced blood-spinal cord barrier (BSCB) disruption. CONCLUSION: These findings strongly suggest that BA may alleviate EAE due to its anti-inflammatory and BSCB protective activities. This indicates that BA is a potential therapeutic agent for treating autoimmune demyelinating diseases including MS.

Dopamine Improves Low Gamma Activities in the Dorsal Striatum of Haloperidol-induced Motor Impairment Mice.

BACKGROUND/AIM: The dorsal striatum is a brain area integrating information for movement output. The local field potentials (LFPs) reflect the neuronal activity that can be used for monitoring brain activities and controlling movement. MATERIALS AND METHODS: Rhythmic low gamma power activity (30.1-45 Hz) in the dorsal striatum was monitored according to voluntary motor movement in rotarod and bar tests in 0.5 mg/kg haloperidol-induced mice. RESULTS: Haloperidol can effectively induce movement impairment indicated by decreased low gamma LFP with the lessened rotarod test's latency fall, and the enhanced bar test's descending latency. L-DOPA was used for the induction of a dopamine-dependent signal. The results showed that 25 mg/kg of L-DOPA could reverse the effect of haloperidol by enhancing low gamma oscillation concomitantly with the improvement in behavioral movement as fast as 60 min after administration, suggesting that dopamine signaling increases low gamma frequency of LFP in correlation with the improved mice movement. This work supports quantitative LFP assessment as a monitoring tool to track drug action on the nervous system. CONCLUSION: In animal models of motor impairment, oral dopaminergic treatment can be effective in restoring motor dysfunction by stimulating low gamma power activity in the dorsal striatum.

Levodopa-induced dyskinesia is preceded by increased levels of anxiety and motor impairment in Parkinson's disease patients.

Introduction: Dopamine replacement therapy with levodopa is the gold standard treatment of Parkinson's disease (PD); however long-term levodopa use is associated with abnormal involuntary movements known as levodopa-induced dyskinesia (LID) in most patients. LID is not preventable and represents the major limitation of PD treatment.Objective: This study was aimed to find clinical and behavioral features that could be used to identify, years in advance, PD patients that are at high risk of developing LID in the future. Method: Data from PD patients enrolled in The Parkinson's progression markers initiative (PPMI, Michael J. Fox Foundation) that developed dyskinesia during their participation in the study were compared with those who did not, and with healthy controls.Result: LID was preceded byhigher levels of trait anxiety and increased motor impairment in PD patients. Additionally, younger age at PD diagnosis, earlier need for dopaminergic therapy and higher initial levodopa dose, were associated with future development of dyskinesia.Conclusion: These findings suggest that easily detectable clinical and behavioral alterations may help to identify PD patients that are more susceptible to develop LID.

4-Phenylbutyrate Mitigates the Motor Impairment and Dopaminergic Neuronal Death During Parkinson's Disease Pathology via Targeting VDAC1 Mediated Mitochondrial Function and Astrocytes Activation.

Parkinson's disease (PD) is a progressive motor neurodegenerative disorder significantly associated with protein aggregation related neurodegenerative mechanisms. In view of no disease modifying drugs, the present study was targeted to investigate the therapeutic effects of pharmacological agent 4-phenylbutyric acid (4PBA) in PD pathology. 4PBA is an FDA approved monocarboxylic acid with inhibitory activity towards histone deacetylase and clinically treats urea cycle disorder. First, we observed the significant protective effects of 4PBA on PD specific neuromuscular coordination, level of tyrosine hydroxylase, α-synuclein level and neurotransmitter dopamine in both substantia nigra and striatal regions of the experimental rat model of PD. Further results revealed that treatment with 4PBA drug exhibited significant protection against disease related oxidative stress and augmented nitrite levels. The disease pathology-related depletion in mitochondrial membrane potential and augmented level of calcium as well as mitochondrion membrane located VDAC1 protein level and cytochrome-c translocation were also significantly attenuated with 4PBA administration. Inhibited neuronal apoptosis and restored neuronal morphology were also observed with 4PBA treatment as measured by level of pro-apoptotic proteins t-Bid, Bax and cleaved caspase-3 along with cresyl violet staining in both substantia nigra and striatal regions. Lastly, PD-linked astrocyte activation was significantly inhibited with 4PBA treatment. Altogether, our findings suggest that 4PBA exerts broad-spectrum neuroprotective effects in PD animal model.

The Lack of Systemic and Subclinical Side Effects of Botulinum Neurotoxin Type-A in Patients Affected by Post-Stroke Spasticity: A Longitudinal Cohort Study.

Botulinum Neurotoxin type-A (BoNT-A) is the treatment of choice for focal post-stroke spasticity (PSS). Due to its mechanism of action and the administration method, some authors raised concern about its possible systemic diffusion leading to contralateral muscle weakness and autonomic nervous system (ANS) alterations. Stroke itself is a cause of motor disability and ANS impairment; therefore, it is mandatory to prevent any source of additional loss of strength and adjunctive ANS disturbance. We enrolled 15 hemiparetic stroke survivors affected by PSS already addressed to BoNT-A treatment. Contralateral handgrip strength and ANS parameters, such as heart rate variability, impedance cardiography values, and respiratory sinus arrythmia, were measured 24 h before (T0) and 10 days after (T1) the ultrasound (US)-guided BoNT-A injection. At T1, neither strength loss nor modification of the basal ANS patterns were found. These findings support recent literature about the safety profile of BoNT-A, endorsing the importance of the US guide for a precise targeting and the sparing of "critical" structures as vessels and nerves.

Protective effects of cyclosporine A on neurodegeneration and motor impairment in rotenone-induced experimental models of Parkinson's disease.

The development of neuroprotective drugs targeting mitochondria could be an important strategy in combating the progressive clinical course of Parkinson's disease. In the current study, we demonstrated that in SH-SY5Y cells (human dopaminergic neuroblastoma cell line), rotenone caused a dose-dependent (0.25-1 µM) and time-dependent (up to 48 h) loss of cell viability and a loss of cellular ATP content with mitochondrial membrane depolarization and an increased formation of reactive oxygen species; all these processes were markedly prevented by the mitochondrial permeability transition pore blocker cyclosporine A, which did not affect complex I inhibition by rotenone. The nuclear morphology of rotenone-treated cells for 48 h indicated the presence of both necrosis and apoptosis. We then examined the effects of cyclosporine A on the rotenone-induced model of Parkinson's disease in Wistar rats. Cyclosporine A significantly improved the motor deficits and prevented the loss of nigral dopaminergic neurons projecting into the striatum in rotenone-treated rats. Being a marketed immuno-suppressive drug, cyclosporine A should be further evaluated for its putative neuroprotective action in Parkinson's disease.

Phosphodiesterase 9 inhibition prolongs the antiparkinsonian action of l-DOPA in parkinsonian non-human primates.

Phosphodiesterase 9 (PDE9) degrades selectively the second messenger cGMP, which is an important molecule of dopamine signaling pathways in striatal projection neurons (SPNs). In this study, we assessed the effects of a selective PDE9 inhibitor (PDE9i) in the primate model of Parkinson's disease (PD). Six macaques with advanced parkinsonism were used in the study. PDE9i was administered as monotherapy and co-administration with l-DOPA at two predetermined doses (suboptimal and threshold s.c. doses of l-Dopa methyl ester plus benserazide) using a controlled blinded protocol to assess motor disability, l-DOPA -induced dyskinesias (LID), and other neurologic drug effects. While PDE9i was ineffective as monotherapy, 2.5 and 5 mg/kg (s.c.) of PDE9i significantly potentiated the antiparkinsonian effects of l-DOPA with a clear prolongation of the "on" state (p < 0.01) induced by either the suboptimal or threshold l-DOPA dose. Co-administration of PDE9i had no interaction with l-DOPA pharmacokinetics. PDE9i did not affect the intensity of LID. These results indicate that cGMP upregulation interacts with dopamine signaling to enhance the l-DOPA reversal of parkinsonian motor disability. Therefore, striatal PDE9 inhibition may be further explored as a strategy to improve motor responses to l-DOPA in PD.

Murine glial progenitor cells transplantation and synthetic PreImplantation Factor (sPIF) reduces inflammation and early motor impairment in ALS mice.

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuronal disorder characterized by neuronal degeneration and currently no effective cure is available to stop or delay the disease from progression. Transplantation of murine glial-restricted precursors (mGRPs) is an attractive strategy to modulate ALS development and advancements such as the use of immune modulators could potentially extend graft survival and function. Using a well-established ALS transgenic mouse model (SOD1G93A), we tested mGRPs in combination with the immune modulators synthetic PreImplantation Factor (sPIF), Tacrolimus (Tac), and Costimulatory Blockade (CB). We report that transplantation of mGRPs into the cisterna magna did not result in increased mice survival. The addition of immunomodulatory regimes again did not increase mice lifespan but improved motor functions and sPIF was superior compared to other immune modulators. Immune modulators did not affect mGRPs engraftment significantly but reduced pro-inflammatory cytokine production. Finally, sPIF and CB reduced the number of microglial cells and prevented neuronal number loss. Given the safety profile and a neuroprotective potential of sPIF, we envision its clinical application in near future.

Efficacy of Corticosteroid Therapy for HTLV-1-Associated Myelopathy: A Randomized Controlled Trial (HAMLET-P).

Corticosteroids are most commonly used to treat HTLV-1-associated myelopathy (HAM); however, their clinical efficacy has not been tested in randomized clinical trials. This randomized controlled trial included 8 and 30 HAM patients with rapidly and slowly progressing walking disabilities, respectively. Rapid progressors were assigned (1:1) to receive or not receive a 3-day course of intravenous methylprednisolone in addition to oral prednisolone therapy. Meanwhile, slow progressors were assigned (1:1) to receive oral prednisolone or placebo. The primary outcomes were a composite of ≥1-grade improvement in the Osame Motor Disability Score or ≥30% improvement in the 10 m walking time (10 mWT) at week 2 for rapid progressors and changes from baseline in 10 mWT at week 24 for slow progressors. In the rapid progressor trial, all four patients with but only one of four without intravenous methylprednisolone achieved the primary outcome (p = 0.14). In the slow progressor trial, the median changes in 10 mWT were -13.8% (95% CI: -20.1--7.1; p < 0.001) and -6.0% (95% CI: -12.8-1.3; p = 0.10) with prednisolone and placebo, respectively (p for between-group difference = 0.12). Whereas statistical significance was not reached for the primary endpoints, the overall data indicated the benefit of corticosteroid therapy. (Registration number: UMIN000023798, UMIN000024085).

Serotonin 1A receptor agonist modulation of motor deficits and cortical oscillations by NMDA receptor interaction in parkinsonian rats.

Although serotonin 1A (5-HT1A) receptor agonists are widely used as the additive compound to reduce l-dopa-induced dyskinesia in Parkinson's disease (PD), few studies focused on the effect and mechanism of 5-HT1A receptor agonist on the motor symptoms of PD. Unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats were used and implantation of electrodes was performed in the motor cortex of these rats. So the effect of 5-HT1A receptor agonist 8-OH-DPAT on motor behaviors and oscillatory activities were evaluated. In addition, 8-OH-DPAT combined with D2 receptor antagonist raclopride, NMDA receptor antagonist MK-801, or its agonist d-cycloserine (DCS) were co-administrated. 8-OH-DPAT administration significantly improved spontaneous locomotor activity and asymmetric forepaw function in 6-OHDA-lesioned rats. Meanwhile, 8-OH-DPAT identified selective modulation of the abnormal high beta oscillations (25-40 Hz) in the motor cortex of 6-OHDA-lesioned rats, without inducing pathological finely tuned gamma around 80 Hz. Different from 8-OH-DPAT, l-dopa treatment produced a prolonged improvement on motor performances and differential regulation of high beta and gamma oscillations. However, dopamine D2 receptor antagonist had no influence on the 8-OH-DPAT-mediated-motor behaviors and beta oscillations in 6-OHDA-lesioned rats. In contrast, subthreshold NMDA receptor antagonist MK-801 obviously elevated the 8-OH-DPAT-mediated-motor behaviors, while NMDA receptor agonist DCS partially impaired the 8-OH-DPAT-mediated symptoms in 6-OHDA-lesioned rats. This study suggests that 5-HT1A receptor agonist 8-OH-DPAT improves motor activity and modulates the oscillations in the motor cortex of parkinsonian rats. Different from l-dopa, 8-OH-DPAT administration ameliorates motor symptoms of PD through glutamatergic rather than the dopaminergic pathway.

Motor impairments in early onset schizophrenia.

AIM: Motor impairments are frequent both at and before diagnosis. In childhood, impairments in general fine and gross motor function are among others identified using test batteries, and while elements of coordination are assessed in onset schizophrenia, the assessment of general motor functions is absent. Thus, we aimed to assess general motor function including childhood motor function in adolescents with schizophrenia in comparison with healthy controls and examine clinical correlates to general motor function. METHOD: General fine and gross motor function was assessed using two standardized age-normed test batteries and a questionnaire in 25 adolescents with schizophrenia compared with age and gender-matched controls using t-test and χ2 -test. Stepwise linear regression assessed potential developmental predictors on motor function including complications during childbirth, reported childhood motor function, executive function including false discovery rate q-values. Associations with schizophrenia symptom severity, executive function, cognitive function were assessed using Pearson's correlation and the impact of antipsychotic medication using t-test. RESULT: All measures of motor function but one significantly differentiated adolescents with schizophrenia from healthy controls. The presence of schizophrenia (ß =4.41, ß = 10.96), explained the main part of the variance however, childhood motor function (ß = .08) also added significantly to motor function. Executive function (ß = -.45) was important for childhood motor function. Severity of schizophrenia was associated with strength (p < .0011) and manual coordination (p = .0295), and receiving antipsychotics affected manual dexterity (p = .0378). CONCLUSION: The documentation of significant differences in general motor function in early onset schizophrenia compared with healthy controls highlights the need for general motor assessments and potential interventions.

Epibrassinolide prevents tau hyperphosphorylation via GSK3ß inhibition in vitro and improves Caenorhabditis elegans lifespan and motor deficits in combination with roscovitine.

Glycogen synthase kinase 3ß (GSK3ß) is considered an important element of glycogen metabolism; however, it has many other regulatory roles. Changes in the GSK3ß signaling mechanism have been associated with various disorders, such as Alzheimer's disease (AD), type II diabetes, and cancer. Although the effects of GSK3ß inhibitors on reducing the pathological effects of AD have been described, an effective inhibitor has not yet been developed. Epibrassinolide (EBR), a brassinosteroid (BR), is structurally similar to mammalian steroid hormones. Our studies have shown that EBR has an inhibitory effect on GSK3ß in different cell lines. Roscovitine (ROSC), a cyclin-dependent kinase (CDK) inhibitor, has also been identified as a potential GSK3 inhibitor. Within the scope of this study, we propose that EBR and/or ROSC might have mechanistic action in AD models. To test this hypothesis, we used in vitro models and Caenorhabditis elegans (C. elegans) AD strains. Finally, EBR treatment successfully protected cells from apoptosis and increased the inhibitory phosphorylation of GSK3ß. In addition, EBR and/or ROSC treatment had a positive effect on the survival rates of C. elegans strains. More interestingly, the paralysis phenotype of the C. elegans AD model due to Aß42 toxicity was prevented by EBR and/or ROSC. Our findings suggest that EBR and ROSC administration have neuroprotective effects on both in vitro and C. elegans models via inhibitory GSK3ß phosphorylation at Ser9.

Targeting TDP-43 Pathology Alleviates Cognitive and Motor Deficits Caused by Chronic Cerebral Hypoperfusion.

Vascular dementia is one of the most common forms of dementia in aging population. However, the molecular mechanisms involved in development of disease and the link between the cerebrovascular pathology and the cognitive impairments remain elusive. Currently, one common and/or converging neuropathological pathway leading to dementia is the mislocalization and altered functionality of the TDP-43. We recently demonstrated that brain ischemia triggers an age-dependent deregulation of TDP-43 that was associated with exacerbated neurodegeneration. Here, we report that chronic cerebral hypoperfusion in mice (CCH) produced by unilateral common carotid artery occlusion induces cytoplasmic mislocalization of TDP-43 and formation of insoluble phosho-TDP-43 aggregates reminiscent of pathological changes detected in cortical neurons of human brain samples from patients suffering from vascular dementia. Moreover, the CCH in mice caused chronic activation of microglia and innate immune response, development of cognitive deficits, and motor impairments. Oral administration of a novel analog (IMS-088) of withaferin A, an antagonist of nuclear factor-κB essential modulator (NEMO), led to mitigation of TDP-43 pathology, enhancement of autophagy, and amelioration of cognitive/motor deficits in CCH mice. Taken together, our results suggest that targeting TDP-43 pathogenic inclusions may have a disease-modifying effect in dementia caused by chronic brain hypoperfusion.

Rifampicin ameliorates lipopolysaccharide-induced cognitive and motor impairments via inhibition of the TLR4/MyD88/NF-κB signaling pathway in mice.

OBJECTIVES: Aberrant microglial responses promote neuroinflammation in neurodegenerative diseases. However, rifampicin's effect on cognitive and motor sequelae of inflammation remains unknown. Therefore, we investigated whether rifampicin exerts neuroprotection against lipopolysaccharide (LPS)-induced cognitive and motor impairments. METHODS: A mouse model of LPS-induced cognitive and motor impairment was established. Adult C57BL/6 mice were injected intraperitoneally with 25 mg/kg rifampicin 30 min before intraperitoneal microinjection of LPS (750 µg/kg) daily until study end. Treatments and behavioral experiments were performed once daily for 7 days. Behavioral tests and pathological/biochemical assays were performed to evaluate LPS-induced damage to the hippocampus and substantia nigra (SN). RESULTS: Rifampicin attenuated LPS-induced cognitive and motor impairments, based on performance in the behavioral tests. Rifampicin suppressed the release of pro-inflammatory mediators, including tumor necrosis factor-α, interleukin-1ß, and prostaglandin E2 in the serum and nitric oxide (NO) in brain tissue, and cyclooxygenase-2 and inducible nitric oxide synthase levels. Immunofluorescence revealed that rifampicin inhibited LPS-induced microglial activation in the hippocampus and SN, thus protecting the neurons. Rifampicin inhibited the activation of the toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/nuclear factor kappa B (NF-κB) signaling pathway. Rifampicin downregulated TLR4 and MyD88 protein levels and inhibited NF-κB inhibitor alpha and NF-κB inhibitor kinase beta phosphorylation, thus reducing p65 nuclear transfer by inhibiting NF-κB signaling activation in LPS-treated mice. CONCLUSION: Rifampicin protects against LPS-induced neuroinflammation and attenuates cognitive and motor impairments by inhibiting the TLR4/MyD88/NF-κB signaling pathway. Our findings might aid the development of novel therapies to treat progressive neurodegenerative diseases.

Neuroprotective effect of ketamine against TNF-α-induced necroptosis in hippocampal neurons.

Tumour necrosis factor-α (TNF-α), a crucial cytokine, has various homeostatic and pathogenic bioactivities. The aim of this study was to assess the neuroprotective effect of ketamine against TNF-α-induced motor dysfunction and neuronal necroptosis in male C57BL/6J mice in vivo and HT-22 cell lines in vitro. The behavioural testing results of the present study indicate that ketamine ameliorated TNF-α-induced neurological dysfunction. Moreover, immunohistochemical staining results showed that TNF-α-induced brain dysfunction was caused by necroptosis and microglial activation, which could be attenuated by ketamine pre-treatment inhibiting reactive oxygen species production and mixed lineage kinase domain-like phosphorylation in hippocampal neurons. Therefore, we concluded that ketamine may have neuroprotective effects as a potent inhibitor of necroptosis, which provides a new theoretical and experimental basis for the application of ketamine in TNF-α-induced necroptosis-associated diseases.