Neuroprotection In Parkinson's Disease Research Articles

JWA binding to NCOA4 alleviates degeneration in dopaminergic neurons through suppression of ferritinophagy in Parkinson's disease

Parkinson's disease (PD) poses a significant challenge in neurodegenerative disorders, characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). The intricate mechanisms orchestrating DA neurodegeneration in PD are not fully understood, necessitating the exploration of innovative therapeutic approaches. Recent studies have implicated ferroptosis as a major contributor to the loss of DA neurons, revealing a complex interplay between iron accumulation and neurodegeneration. However, the sophisticated nature of this process challenges the conventional belief that mere iron removal could effectively prevent DA neuronal ferroptosis. Here, we report JWA, alternatively referred to as ARL6IP5, as a negative regulator of ferroptosis, capable of ameliorating DA neuronal loss in the context of PD. In this study, synchronized expression patterns of JWA and tyrosine hydroxylase (TH) in PD patients and mice were observed, underscoring the importance of JWA for DA neuronal survival. Screening of ferroptosis-related genes unraveled the engagement of iron metabolism in the JWA-dependent inhibition of DA neuronal ferroptosis. Genetic manipulation of JWA provided compelling evidence linking its neuroprotective effects to the attenuation of NCOA4-mediated ferritinophagy. Molecular docking, co-immunoprecipitation, and immunofluorescence studies confirmed that JWA mitigated DA neuronal ferroptosis by occupying the ferritin binding site of NCOA4. Moreover, the JWA-activating compound, JAC4, demonstrated promising neuroprotective effects in cellular and animal PD models by elevating JWA expression, offering a potential avenue for neuroprotection in PD. Collectively, our work establishes JWA as a novel regulator of ferritinophagy, presenting a promising therapeutic target for addressing DA neuronal ferroptosis in PD.

Nonintuitive Immunogenicity and Plasticity of Alpha-Synuclein Conformers: A Paradigm for Smart Delivery of Neuro-Immunotherapeutics.

Despite the extensive research successes and continuous developments in modern medicine in terms of diagnosis, prevention, and treatment, the lack of clinically useful disease-modifying drugs or immunotherapeutic agents that can successfully treat or prevent neurodegenerative diseases is an ongoing challenge. To date, only one of the 244 drugs in clinical trials for the treatment of neurodegenerative diseases has been approved in the past decade, indicating a failure rate of 99.6%. In corollary, the approved monoclonal antibody did not demonstrate significant cognitive benefits. Thus, the prevalence of neurodegenerative diseases is increasing rapidly. Therefore, there is an urgent need for creative approaches to identifying and testing biomarkers for better diagnosis, prevention, and disease-modifying strategies for the treatment of neurodegenerative diseases. Overexpression of the endogenous α-synuclein has been identified as the driving force for the formation of the pathogenic α-synuclein (α-Syn) conformers, resulting in neuroinflammation, hypersensitivity, endogenous homeostatic responses, oxidative dysfunction, and degeneration of dopaminergic neurons in Parkinson's disease (PD). However, the conformational plasticity of α-Syn proffers that a certain level of α-Syn is essential for the survival of neurons. Thus, it exerts both neuroprotective and neurotoxic (regulatory) functions on neighboring neuronal cells. Furthermore, the aberrant metastable α-Syn conformers may be subtle and difficult to detect but may trigger cellular and molecular events including immune responses. It is well documented in literature that the misfolded α-Syn and its conformers that are released into the extracellular space from damaged or dead neurons trigger the innate and adaptive immune responses in PD. Thus, in this review, we discuss the nonintuitive plasticity and immunogenicity of the α-Syn conformers in the brain immune cells and their physiological and pathological consequences on the neuroimmune responses including neuroinflammation, homeostatic remodeling, and cell-specific interactions that promote neuroprotection in PD. We also critically reviewed the novel strategies for immunotherapeutic delivery interventions in PD pathogenesis including immunotherapeutic targets and potential nanoparticle-based smart drug delivery systems. It is envisioned that a greater understanding of the nonintuitive immunogenicity of aberrant α-Syn conformers in the brain's microenvironment would provide a platform for identifying valid therapeutic targets and developing smart brain delivery systems for clinically effective disease-modifying immunotherapeutics that can aid in the prevention and treatment of PD in the future.

Neuronal deletion of the circadian clock gene Bmal1 induces cell-autonomous dopaminergic neurodegeneration.

Circadian rhythm dysfunction is a hallmark of Parkinson disease (PD), and diminished expression of the core clock gene Bmal1 has been described in patients with PD. BMAL1 is required for core circadian clock function but also serves nonrhythmic functions. Germline Bmal1 deletion can cause brain oxidative stress and synapse loss in mice, and it can exacerbate dopaminergic neurodegeneration in response to the toxin MPTP. Here we examined the effect of cell type-specific Bmal1 deletion on dopaminergic neuron viability in vivo. We observed that global, postnatal deletion of Bmal1 caused spontaneous loss of tyrosine hydroxylase+ (TH+) dopaminergic neurons in the substantia nigra pars compacta (SNpc). This was not replicated by light-induced disruption of behavioral circadian rhythms and was not induced by astrocyte- or microglia-specific Bmal1 deletion. However, either pan-neuronal or TH neuron-specific Bmal1 deletion caused cell-autonomous loss of TH+ neurons in the SNpc. Bmal1 deletion did not change the percentage of TH neuron loss after α-synuclein fibril injection, though Bmal1-KO mice had fewer TH neurons at baseline. Transcriptomics analysis revealed dysregulation of pathways involved in oxidative phosphorylation and Parkinson disease. These findings demonstrate a cell-autonomous role for BMAL1 in regulating dopaminergic neuronal survival and may have important implications for neuroprotection in PD.

Neuroprotective Effect of Mangiferin against Parkinson's Disease through G-Protein-Coupled Receptor-Interacting Protein 1 (GIT1)-Mediated Antioxidant Defense.

Parkinson's disease (PD), known as a neurodegenerative disease, is characterized by movement disorders, with increasing age being the predominant risk factor for its development. Mangiferin, a bioactive compound isolated from mango, shows potent neuroprotection. In our work, we investigated the neuroprotection and mechanisms of mangiferin against PD. We established PD models by treating SH-SY5Y cells with rotenone and mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and investigated the therapeutic effects of mangiferin. Our results showed that mangiferin exhibited a cell-protective effect. Mangiferin also improved the motor behavior and attenuated the activation of microglia and astrocytes in MPTP mice. In addition, mangiferin decreased reactive oxygen species (ROS) levels and increased glutathione (GSH) and superoxide dismutase (SOD). Mangiferin also markedly activated GIT1, p-ERK, Nrf2, HO-1, and SOD expression and inhibited Keap1 expression in vitro and in vivo. To further investigate the role of GIT1, GIT1 siRNA was used. In the presence of GIT1 siRNA, the neuroprotection of mangiferin in PD was weakened. Our results indicate that mangiferin exhibited its therapeutic effect against PD by regulating GIT1 and its downstream Keap1/Nrf2 pathways. Our studies exhibited that mangiferin showed neuroprotection in PD, and its main target was GIT1. What is more, mangiferin could reduce the oxidative stress of PD by targeting GIT1 and its downstream Keap1/Nrf2 pathways. These indicated that mangiferin is a good candidate for PD therapy. However, the role of p-ERK in mangiferin-treated PD requires further investigation.

Gut-Brain Communication in Parkinson's Disease: Enteroendocrine Regulation by GLP-1.

Defective gut-brain communication has recently been proposed as a promoter of neurodegeneration, but mechanisms mediating communication remain elusive. In particular, the Parkinson's disease (PD) phenotype has been associated with both dysbiosis of intestinal microbiota and neuroinflammation. Here, we review recent advances in the PD field that connect these two concepts, providing an explanation based on enteroendocrine signaling from the gut to the brain. There have been several recent accounts highlighting the importance of the microbiota-gut-brain axis in PD. The objective of this review is to discuss the role of the neuroendocrine system in gut-brain communication as it relates to PD pathogenesis, as this system has not been comprehensively considered in prior reviews. The incretin hormone glucagon-like peptide 1 (GLP-1) is secreted by enteroendocrine cells of the intestinal epithelium, and there is evidence that it is neuroprotective in animal models and human subjects with PD. Agonists of GLP-1 receptors used in diabetes appear to be useful for preventing neurodegeneration. New tools and models have enabled us to study regulation of GLP-1 secretion by intestinal microbiota, to understand how this process may be defective in PD, and to develop methods for therapeutically modifying disease development or progression using the enteroendocrine system. GLP-1 secretion by enteroendocrine cells may be a key mediator of neuroprotection in PD, and new findings in this field may offer unique insights into PD pathogenesis and therapeutic strategies.

Nano-MgO composites containing plasmid DNA to silence SNCA gene displays neuroprotective effects in Parkinson's rats induced by 6-hydroxydopamine

Parkinson's disease (PD) always causes dyskinesia and cognitive impairments. The alpha-synuclein (α-syn) accumulation, one of the main pathological characteristics of PD, may impair synaptic structural and synaptic functions. Nano-MgO composites has been reported to interfere α-syn expression. The present study is aim to investigate the roles of nano-MgO composites on cognitive impairments in PD rats. PD rats were formed by 6-hydroxydopamine (6-OH DA) and α-syn expression were evaluated by Western blot. Hippocampal dendritic morphology was examined by Golgi staining. Morris water maze (MWM) test was applied to evaluate learning and memory abilities and population spike was recorded by electrophysiological records in vivo. The results showed that: 6-OH DA-treated up-regulated α-syn levels in striatum and hippocampus and increased the rotational times by APO, but nano-MgO composites could down-regulated α-syn levels. The overall length of dendritic and the total number of intersections were reduced by 6-OH DA, accompanied by the decrease of the dendritic spine density in hippocampal CA1, CA3 and DG regions. Interestingly, nano-MgO composites could alleviate the morphological damages of dendrites. In the MWM test, the escape latencies and the swimming distances in PD rats were increased as compared to the sham group, and nano-MgO composites could reduce the escapes latencies and the swimming distances. Furthermore, 6-OH DA reduced the amplitudes of long-term potentiation (LTP) in hippocampal CA1 region, and 6 mg/kg nano-MgO composites could improve LTP amplitudes. In conclusion, the current findings would be helpful to explore the roles of nano-MgO composites on neuroprotection in PD.

The Protective Effects of Mogroside V Against Neuronal Damages by Attenuating Mitochondrial Dysfunction via Upregulating Sirtuin3.

Mitochondrial dysfunction and oxidative stress are thought to play a dominant role in the pathogenesis of Parkinson's disease (PD). Mogroside V (MV), extracted from Siraitia grosvenorii, exhibits antioxidant-like activities. The aim of this study was to investigate the function of MV in neuroprotection in PD and to reveal its mechanism of action. To that end, we firstly set up mice models of PD with unilateral striatum injection of 0.25mg/kg rotenone (Rot) and co-treated with 2.5mg/kg, 5mg/kg, and 10mg/kg MV by gavage. Results showed that Rot-induced motor impairments and dopaminergic neuronal damage were reversed by treatment of 10mg/kg MV. Then, we established cellular models of PD using Rot-treated SH-SY5Y cells, which were divided into six groups, including control, Rot, and co-enzyme Q10 (CQ10), as well as MV groups, MV25, MV50, and MV100 treated with 25μM, 50μM, and 100μM MV doses, respectively. Results demonstrated that MV effectively attenuates Rot neurotoxicity through a ROS-related intrinsic mitochondrial pathway. MV reduced overproduction of reactive oxygen species (ROS), recovered the mitochondrial membrane potential(MMP), and increased the oxygen consumption rate and adenosine triphosphate (ATP) production in a dose-dependent manner. Hence, treatment with MV led to a reduction in the number of apoptotic cells, as reflected by Annexin-V/propidium iodide co-staining using flow cytometry and TdT-mediated dUTP Nick-End Labeling (TUNEL) assay. In addition, the Sirtuin3 (SIRT3) protein level and activity were decreased upon exposure to Rot both in substantia nigra (SN) of mice and SH-SY5Y cells. SIRT3 impairment hyperacetylated a key mitochondrial antioxidant enzyme, superoxide dismutase 2 (SOD2). MV alleviates SIRT3 and SOD2 molecular changes. However, after successfully inhibiting SIRT3 by its specific inhibitor 3-1H-1, 2, 3-triazol-4-yl pyridine (3TYP), MV was not able to reduce ROS levels, reverse abnormal MMP, or decrease apoptotic cells. Motor impairments and dopaminergic neuronal injury in the SN were alleviated with the oral administration of MV in Rot-treated PD mice, indicating a relationship between protection against defective motility and preservation of dopaminergic neurons. Therefore, we conclude that MV can alleviate Rot-induced neurotoxicity in a PD model, and that SIRT3 may be an important regulator in the protection of MV.

Neuroprotective effect of bromelain in 6-hydroxydopamine induced in vitro model of Parkinson's disease.

This study was designed to investigate the neuroprotective effects of bromelain, which is known to have anti-oxidant and anti-inflammatory properties, against the neurotoxicity (induced by 6-OHDA) in SH-SY5Y cells. To establish Parkinson's Disease (PD) model in cell culture conditions, SH-SY5Y cells were exposed to 200 µM 6-OHDA for 1day. Prior to 6-OHDA treatment, SH-SY5Y cells had been pre-treated with bromelain (25µg/mL, 50µg/mL, 75µg/mL and 100µg/mL). After 1day, cell viability was determined with the 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) and lactate dehydrogenase (LDH) assays. Oxidative stress was assessed with total antioxidant capacity (TAC), total oxidant status (TOS), glutathione reductase (GR) and malondialdehyde (MDA) analyses. The effect of the bromelain in SH-SY5Ycells was also examined by 4',6-diamidino-2-phenylindole (DAPI) staining. We found that 6-OHDA increased LDH leakage, and cellular apoptosis in SH-SY5Y cells. 6-OHDA aggravated oxidative stress by increasing TOS, MDA and GR and eventually promoted apoptosis in SH-SY5Y cells, while pretreatment with bromelain attenuated these toxic effects of 6-OHDA. These findings indicated that bromelain, with its neuroprotective features can be useful for neuroprotection in PD.

A Novel, Selective c-Abl Inhibitor, Compound 5, Prevents Neurodegeneration in Parkinson’s Disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects movement. The nonreceptor tyrosine kinase c-Abl has shown a potential role in the progression of PD. As such, c-Abl inhibition is a promising candidate for neuroprotection in PD and α-synucleinopathies. Compound 5 is a newly synthesized blood-brain barrier penetrant c-Abl inhibitor with higher efficacy than existing inhibitors. The objective of the current study was to demonstrate the neuroprotective effects of compound 5 on the α-synuclein preformed fibril (α-syn PFF) mouse model of PD. Compound 5 significantly reduced neurotoxicity, activation of c-Abl, and Lewy body pathology caused by α-syn PFF in cortical neurons. Additionally, compound 5 markedly ameliorated the loss of dopaminergic neurons, c-Abl activation, Lewy body pathology, neuroinflammatory responses, and behavioral deficits induced by α-syn PFF injection in vivo. Taken together, these results suggest that compound 5 could be a pharmaceutical agent to prevent the progression of PD and α-synucleinopathies.

Striatal Afferent BDNF Is Disrupted by Synucleinopathy and Partially Restored by STN DBS.

Preclinical studies show a link between subthalamic nucleus (STN) deep brain stimulation (DBS) and neuroprotection of nigrostriatal dopamine (DA) neurons, potentially through brain-derived neurotrophic factor (BDNF) signaling. However, the question of whether DBS of the STN can be disease-modifying in Parkinson's disease (PD) remains unanswered. In particular, the impact of STN DBS on α-synuclein (α-syn) aggregation, inclusion-associated neuroinflammation, and BDNF levels has yet to be examined in the context of synucleinopathy. To address this, we examined the effects of STN DBS on BDNF using the α-syn preformed fibril (PFF) model in male rats. While PFF injection resulted in accumulation of phosphorylated α-syn (pSyn) inclusions in the substantia nigra pars compacta (SNpc) and cortical areas, STN DBS did not impact PFF-induced accumulation of pSyn inclusions in the SNpc. In addition, nigral pSyn inclusions were associated with increased microgliosis and astrogliosis; however, the magnitude of these processes was not altered by STN DBS. Total BDNF protein was not impacted by pSyn inclusions, but the normally positive association of nigrostriatal and corticostriatal BDNF was reversed in rats with PFF-induced nigrostriatal and corticostriatal inclusions. Despite this, rats receiving both STN DBS and PFF injection showed increased BDNF protein in the striatum, which partially restored the normal corticostriatal relationship. Our results suggest that pathologic α-syn inclusions disrupt anterograde BDNF transport within nigrostriatal and corticostriatal circuitry. Further, STN DBS has the potential to exert protective effects by modifying the long-term neurodegenerative consequences of synucleinopathy.SIGNIFICANCE STATEMENT An increase in brain-derived neurotrophic factor (BDNF) has been linked to the neuroprotection elicited by subthalamic nucleus (STN) deep brain stimulation (DBS) in neurotoxicant models of Parkinson's disease (PD). However, whether STN DBS can similarly increase BDNF in nigrostriatal and corticostriatal circuitry in the presence of α-synuclein (α-syn) inclusions has not been examined. We examined the impact of STN DBS on rats in which accumulation of α-syn inclusions is induced by injection of α-syn preformed fibrils (PFFs). STN DBS significantly increased striatal BDNF protein in rats seeded with α-syn inclusions and partially restored the normal corticostriatal BDNF relationship. These findings suggest that STN DBS can drive BDNF in the parkinsonian brain and retains the potential for neuroprotection in PD.

Therapeutic strategy for Parkinson's disease: targeting zinc-binding protein in astrocytes

Parkinson's disease (PD) is a progressive neurodegenerative disease with motor symptoms, such as tremor, akinesia/bradykinesia, rigidity and postural instability due to a loss of nigrostriatal dopaminergic neurons; PD patients also exhibit non-motor symptoms, such as hyposmia, orthostatic hypotension and constipation, which precede motor symptoms. Pathologically, Lewy bodies and neurites, which contains α-synuclein, are observed in the central and peripheral nervous system. To date, it is hypothesized that PD pathology appears first in the olfactory bulb and the enteric nervous system, and propagates progressively through the substantia nigra to finally reach the cerebral cortex. Major medications at present are nosotropic treatments to improve motor dysfunction in PD. Therefore, development of disease-modifying drug is required to slow or prevent PD progression. Astrocytes are known to play an important role in the maintenance of the neuronal environment and exert neuroprotective effects by production of antioxidants and neurotrophic factors and clearing toxic molecules. In the previous study, we demonstrated that astrocytes produced antioxidative molecules metallothionein (MT)-1/2 in response to oxidative stress and protected dopaminergic neurons against oxidative stress. MTs are cysteine-rich proteins possessing antioxidative properties. MTs bind to metals such as zinc (Zn) and copper (Cu) and function in metal homeostasis and detoxification; MTs regulate Zn-mediated transcriptional activation of various genes. Recently, it is reported that MTs prevent Cu-induced aggregation of α-synuclein. In this article, we review a new therapeutic strategy of neuroprotection in PD by targeting MTs in astrocytes.

Histamine H3 and H4 receptors modulate Parkinson's disease induced brain pathology. Neuroprotective effects of nanowired BF-2649 and clobenpropit with anti-histamine-antibody therapy.

Military personnel deployed in combat operations are highly prone to develop Parkinson's disease (PD) in later lives. PD largely involves dopaminergic pathways with hallmarks of increased alpha synuclein (ASNC), and phosphorylated tau (p-tau) in the cerebrospinal fluid (CSF) precipitating brain pathology. However, increased histaminergic nerve fibers in substantia nigra pars Compacta (SNpc), striatum (STr) and caudate putamen (CP) associated with upregulation of Histamine H3 receptors and downregulation of H4 receptors in human cases of PD is observed in postmortem cases. These findings indicate that modulation of histamine H3 and H4 receptors and/or histaminergic transmission may induce neuroprotection in PD induced brain pathology. In this review effects of a potent histaminergic H3 receptor inverse agonist BF-2549 or clobenpropit (CLBPT) partial histamine H4 agonist with H3 receptor antagonist, in association with monoclonal anti-histamine antibodies (AHmAb) in PD brain pathology is discussed based on our own observations. Our investigation shows that chronic administration of conventional or TiO2 nanowired BF 2649 (1mg/kg, i.p.) or CLBPT (1mg/kg, i.p.) once daily for 1 week together with nanowired delivery of HAmAb (25μL) significantly thwarted ASNC and p-tau levels in the SNpC and STr and reduced PD induced brain pathology. These observations are the first to show the involvement of histamine receptors in PD and opens new avenues for the development of novel drug strategies in clinical strategies for PD, not reported earlier.

LncRNA NEAT1 Regulates the Development of Parkinson's Disease by Targeting AXIN1 Via Sponging miR-212-3p.

Long non-coding RNA (lncRNA) nuclear-enriched assembly transcript 1 (NEAT1) has been reported to be highly expressed in Parkinson's disease (PD). However, the mechanism of NEAT1 in PD progression has not been fully elucidated. 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine injection (MPTP) was used to construct PD mouse models in vivo, and 1-methyl-4-phenyl pyridine (MPP+) was used to build PD cell models in vitro. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to test the expression of NEAT1, microRNA (miR)-212-3p and axis inhibition protein 1 (AXIN1). The viability, apoptosis and inflammation of cells were determined using cell counting kit 8 (CCK8) assay, flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively. Then, the protein levels of apoptosis-related markers and AXIN1 were measured by western blot (WB) analysis. Furthermore, dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were performed to verify the interaction between miR-212-3p and NEAT1 or AXIN1. NEAT1 was upregulated in PD mouse models and cell models. Function experiments confirmed that NEAT1 knockdown could promote the viability, suppress the apoptosis and inflammation of MPP+-stimulated SK-N-SH cells to restrain PD progression. MiR-212-3p was downregulated in PD, and its inhibitor could reverse the suppression effect of NEAT1 knockdown on PD progression. Additionally, AXIN1 was a target of miR-212-3p, and its overexpression could invert the inhibition effect of miR-212-3p mimic on PD progression. Furthermore, AXIN1 expression was inhibited by NEAT1 silencing and promoted by NEAT1 overexpression, while these effect could be recovered by miR-212-3p inhibitor and mimic, respectively. Our results demonstrated that NEAT1 knockdown suppressed PD progression through regulating the miR-212-3p/AXIN1 pathway, indicating that NEAT1 might be a therapeutic target for neuroprotection in PD.

The beneficial effect of vanillin on 6-hydroxydopamine rat model of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is related to neuroinflammation. Vanillin, which possesses both antioxidant, and anti-inflammatory properties, can be a candidate for neuroprotection in PD. This study was aimed to investigate the effects of vanillin on the 6-hydroxydopamine (6-OHDA) rodent model of PD. Male Wistar rats were administrated intraperitoneal (i.p) or oral vanillin at a dose of 20 mg/kg/day for 7 days that was started at three days before or seven days after intracerebral injection of 6-OHDA. The 6-OHDA-induced lesions were assessed behaviorally using the apomorphine rotation test, neurochemically via measuring striatal dopamine concentrations, and through immunohistochemistry. Both oral and IP vanillin at three days before or seven days after 6-OHDA lesioning exhbited significantly lower tight contralateral rotations upon apomorphine challenge, and higher striatal dopamine concentrations. Vanillin seems to offer protective properties against 6-OHDA lesion via preserving striatal dopamine levels.

Enhanced activity of glycolytic enzymes in Drosophila and human cell models of Parkinson's disease based on DJ-1 deficiency

Parkinson's disease (PD) is a neurodegenerative debilitating disorder characterized by progressive disturbances in motor, autonomic and psychiatric functions. One of the genes involved in familial forms of the disease is DJ-1, whose mutations cause early-onset PD. Besides, it has been shown that an over-oxidized and inactive form of the DJ-1 protein is found in brains of sporadic PD patients. Interestingly, the DJ-1 protein plays an important role in cellular defense against oxidative stress and also participates in mitochondrial homeostasis. Valuable insights into potential PD pathogenic mechanisms involving DJ-1 have been obtained from studies in cell and animal PD models based on DJ-1 deficiency such as Drosophila. Flies mutant for the DJ-1β gene, the Drosophila ortholog of human DJ-1, exhibited disease-related phenotypes such as motor defects, increased reactive oxygen species production and high levels of protein carbonylation. In the present study, we demonstrate that DJ-1β mutants also show a significant increase in the activity of several regulatory glycolytic enzymes. Similar results were obtained in DJ-1-deficient SH-SY5Y neuroblastoma cells, thus suggesting that loss of DJ-1 function leads to an increase in the glycolytic rate. In such a scenario, an enhancement of the glycolytic pathway could be a protective mechanism to decrease ROS production by restoring ATP levels, which are decreased due to mitochondrial dysfunction. Our results also show that meclizine and dimethyl fumarate, two FDA-approved compounds with different clinical applications, are able to attenuate PD-related phenotypes in both models. Moreover, we found that they may exert their beneficial effect by increasing glycolysis through the activation of key glycolytic enzymes. Taken together, these results are consistent with the idea that increasing glycolysis could be a potential disease-modifying strategy for PD, as recently suggested. Besides, they also support further evaluation and potential repurposing of meclizine and dimethyl fumarate as modulators of energy metabolism for neuroprotection in PD.

Xanthine Derivatives as Agents Affecting Non-dopaminergic Neuroprotection in Parkinson`s Disease.

Parkinson's Disease (PD) is a neurodegenerative and debilitating disease that affects 1% of the elderly population. Patient's motor disability results in extreme difficulty to deal with daily activities. Conventional treatment is limited to dopamine replacement therapy, which fails to delay disease's progression and is often associated with a number of adverse reactions. Recent progress in understanding the mechanisms involved in PD has revealed new molecular targets for therapeutic approaches. Among them, caffeine and xanthine derivatives are promising drug candidates, because of the possible symptomatic benefits in PD. In fact, consumption of coffee correlates with a reduced risk of PD. Over the last decades, a lot of efforts have been made to uncover the therapeutic potential of xanthine structures. The substituted xanthine molecule is used as a scaffold for the synthesis of new compounds with protective effects in neurodegenerative diseases, including PD, asthma, cancer and others. The administration of the xanthines has been proposed as a non-dopaminergic strategy for neuroprotection in PD and the mechanisms of protection have been associated with antagonism of adenosine A2A receptors and Monoamine Oxidase type B (MAO-B) inhibition. The current review summarizes frequently suspected non-dopaminergic neuroprotective mechanisms and the possible beneficial effects of the xanthine derivatives in PD, along with some synthetic approaches to produce perspective xanthine derivatives as non-dopaminergic agents in PD treatment.

Mild traumatic brain injury exacerbates Parkinson's disease induced hemeoxygenase-2 expression and brain pathology: Neuroprotective effects of co-administration of TiO2 nanowired mesenchymal stem cells and cerebrolysin.

Mild traumatic brain injury (mTBI) is one of the leading predisposing factors in the development of Parkinson's disease (PD). Mild or moderate TBI induces rapid production of tau protein and alpha synuclein (ASNC) in the cerebrospinal fluid (CSF) and in several brain areas. Enhanced tau-phosphorylation and ASNC alters the molecular machinery of the brain leading to PD pathology. Recent evidences show upregulation of constitutive isoform of hemeoxygenase (HO-2) in PD patients that correlates well with the brain pathology. mTBI alone induces profound upregulation of HO-2 immunoreactivity. Thus, it would be interesting to explore whether mTBI exacerbates PD pathology in relation to tau, ASNC and HO-2 expression. In addition, whether neurotrophic factors and stem cells known to reduce brain pathology in TBI could induce neuroprotection in PD following mTBI. In this review role of mesenchymal stem cells (MSCs) and cerebrolysin (CBL), a well-balanced composition of several neurotrophic factors and active peptide fragments using nanowired delivery in PD following mTBI is discussed based on our own investigation. Our results show that mTBI induces concussion exacerbates PD pathology and nanowired delivery of MSCs and CBL induces superior neuroprotection. This could be due to reduction in tau, ASNC and HO-2 expression in PD following mTBI, not reported earlier. The functional significance of our findings in relation to clinical strategies is discussed.

Therapeutic strategy for Parkinson's disease: Targeting zinc-binding protein in astrocytes

Parkinson's disease (PD) is a progressive neurodegenerative disease with motor symptoms, such as tremor, akinesia/bradykinesia, rigidity and postural instability due to a loss of nigrostriatal dopaminergic neurons; PD patients also exhibit non-motor symptoms, such as hyposmia, orthostatic hypotension and constipation, which precede motor symptoms. Pathologically, Lewy bodies and neurites, which contains α-synuclein, are observed in the central and peripheral nervous system. To date, it is hypothesized that PD pathology appears first in the olfactory bulb and the enteric nervous system, and propagates progressively through the substantia nigra to finally reach the cerebral cortex. Major medications at present are nosotropic treatments to improve motor dysfunction in PD. Therefore, development of disease-modifying drug is required to slow or prevent PD progression. Astrocytes are known to play an important role in the maintenance of the neuronal environment and exert neuroprotective effects by production of antioxidants and neurotrophic factors and clearing toxic molecules. In the previous study, we demonstrated that astrocytes produced antioxidative molecules metallothionein (MT)-1/2 in response to oxidative stress and protected dopaminergic neurons against oxidative stress. MTs are cysteine-rich proteins possessing antioxidative properties. MTs bind to metals such as zinc (Zn) and copper (Cu) and function in metal homeostasis and detoxification; MTs regulate Zn-mediated transcriptional activation of various genes. Recently, it is reported that MTs prevent Cu-induced aggregation of α-synuclein. In this article, we review a new therapeutic strategy of neuroprotection in PD by targeting MTs in astrocytes.

Pharmacological inhibition of CSF1R by GW2580 reduces microglial proliferation and is protective against neuroinflammation and dopaminergic neurodegeneration.

Increased pro-inflammatory cytokine levels and proliferation of activated microglia have been found in Parkinson's disease (PD) patients and animal models of PD, suggesting that targeting of the microglial inflammatory response may result in neuroprotection in PD. Microglial proliferation is regulated by many factors, but colony stimulating factor-1 receptor (CSF1R) has emerged as a primary factor. Using data mining techniques on existing microarray data, we found that mRNA expression of the CSF1R ligand, CSF-1, is increased in the brain of PD patients compared to controls. In two different neurotoxic mouse models of PD, acute MPTP and sub-chronic LPS treatment, mRNA and protein levels of CSF1R and CSF-1 were significantly increased. Treatment with the CSF1R inhibitor GW2580 significantly attenuated MPTP-induced CSF1R activation and Iba1-positive cell proliferation, without a reduction of the basal Iba1-positive population in the substantia nigra. GW2580 treatment also significantly decreased mRNA levels of pro-inflammatory factors, without alteration of anti-inflammatory mediators, and significantly attenuated the MPTP-induced loss of dopamine neurons and motor behavioral deficits. Importantly, these effects were observed in the absence of overt microglial depletion, suggesting that targeting CSF1R signaling may be a viable neuroprotective strategy in PD that disrupts pro-inflammatory signaling, but maintains the beneficial effects of microglia.

The Potential of L-Type Calcium Channels as a Drug Target for Neuroprotective Therapy in Parkinson's Disease.

The motor symptoms of Parkinson's disease (PD) mainly arise from degeneration of dopamine neurons within the substantia nigra. As no disease-modifying PD therapies are available, and side effects limit long-term benefits of current symptomatic therapies, novel treatment approaches are needed. The ongoing phase III clinical study STEADY-PD is investigating the potential of the dihydropyridine isradipine, an L-type Ca2+ channel (LTCC) blocker, for neuroprotective PD therapy. Here we review the clinical and preclinical rationale for this trial and discuss potential reasons for the ambiguous outcomes of in vivo animal model studies that address PD-protective dihydropyridine effects. We summarize current views about the roles of Cav1.2 and Cav1.3 LTCC isoforms for substantia nigra neuron function, and their high vulnerability to degenerative stressors, and for PD pathophysiology. We discuss different dihydropyridine sensitivities of LTCC isoforms in view of their potential as drug targets for PD neuroprotection, and we conclude by considering how these aspects could guide further drug development.