Tubeimoside-1 mediates significant neuroprotection in a 6-OHDA-Induced Parkinson’s disease model: unveiling a potential disease-modifying agent

Delayed Dominant-Negative TNF Gene Therapy Halts Progressive Loss of Nigral Dopaminergic Neurons in a Rat Model of Parkinson's Disease

Proteasome dysfunction has been demonstrated in Parkinson disease (PD), and proteasome inhibitors have been shown to induce degeneration of dopaminergic neurons in vitro and in vivo. The mechanism whereby proteasome dysfunction leads to dopaminergic cell death, however, is unknown. In this study, we show that proteasome inhibition in both PC12 cells and dopaminergic neurons derived from embryonic stem cells is associated with mitochondrial membrane permeabilization, activation of caspase-3, and nuclear changes consistent with apoptosis. Prior to the emergence of apoptotic features, we found that proteasome inhibition induced increased levels of phosphorylated p53. Inhibition of p53 by pifithrin-alpha or by RNA interference prevented mitochondrial membrane permeabilization and cytotoxicity. There was no increase in p53 mRNA in proteasome-inhibited cells, suggesting that p53 was increased in a transcription-independent manner. Further, there was no increase in Puma or Bax mRNA and p53 co-immunoprecipitated with Bcl-xL and Mdm2. These findings suggest that p53 mediates cell death by way of a direct mitochondrial effect in this model. We also observed increased levels of phosphorylated p53 in dopamine neurons of the substantia nigra pars compacta of mice following systemic administration of a proteasome inhibitor. These changes preceded degeneration of dopaminergic neurons. Increased phosphorylated p53 was also demonstrated in the substantia nigra pars compacta of post-mortem PD brains. These results suggest that abnormalities in p53 signaling play a role in dopaminergic cell death induced by proteasome inhibition and may be relevant to neurodegeneration in PD.

Neuroprotective effects of lignan 7-hydroxymatairesinol (HMR/lignan) in a rodent model of Parkinson's disease.

HSP70 and Constitutively Active HSF1 Mediate Protection Against CDCrel-1-mediated Toxicity

Nogo-A belongs to the reticulon family (RTN4) and is generally assumed to be one of the most potent myelin associated neurite outgrowth inhibitors in the central nervous system (CNS). Together with other inhibitors such as the myelin associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp), several semaphorins and ephrins as well as chondriotin sulphate proteoglycans, Nogo-A contributes to a nonpermissive environment in the brain and spinal cord. Based on their seminal observation that neurons grown in close proximity to CNS derived oligodendrocytes showed a robust decrease in neurite outgrowth and number of processes, Schwab and Caroni (1988) postulated for nonpermissive substrate properties present in the CNS myelin. In further studies, they identified a high molecular weight component from the CNS myelin called NI-250 which was later renamed Nogo-A. In the course it could be demonstrated that Nogo-A is expressed on the surface of oligodendrocytes and is responsible for the inhibition of axonal sprouting. Since the nonpermissive environment plays a very important role in brain injuries and neurodegenerative diseases, Nogo-A and its receptors were extensively studied.

Ventral midbrain dopaminergic neurons: From neurogenesis to neurodegeneration

Parkinson disease (PD) is a neurodegenerative disease characterized by progressive dopaminergic neurodegeneration in the substantia nigra pars compacta (SNc) area. The present study was undertaken to evaluate the neuroprotective effect of β-caryophyllene (BCP) against rotenone-induced oxidative stress and neuroinflammation in a rat model of PD. In the present study, BCP was administered once daily for 4weeks at a dose of 50mg/kg body weight prior to a rotenone (2.5mg/kg body weight) challenge to mimic the progressive neurodegenerative nature of PD. Rotenone administration results in oxidative stress as evidenced by decreased activities of superoxide dismutase, catalase, and depletion of glutathione with a concomitant rise in lipid peroxidation product, malondialdehyde. Rotenone also significantly increased pro-inflammatory cytokines in the midbrain region and elevated the inflammatory mediators such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in the striatum. Further, immunohistochemical analysis revealed loss of dopaminergic neurons in the SNc area and enhanced expression of ionized calcium-binding adaptor molecule-1 (Iba-1) and glial fibrillary acidic protein (GFAP), indicators of microglia activation, and astrocyte hypertrophy, respectively, as an index of inflammation. However, treatment with BCP rescued dopaminergic neurons and decreased microglia and astrocyte activation evidenced by reduced Iba-1 and GFAP expression. BCP in addition to attenuation of pro-inflammatory cytokines and inflammatory mediators such as COX-2 and iNOS, also restored antioxidant enzymes and inhibited lipid peroxidation as well as glutathione depletion. The findings demonstrate that BCP provides neuroprotection against rotenone-induced PD and the neuroprotective effects can be ascribed to its potent antioxidant and anti-inflammatory activities.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra pars compacta. In this study, we investigated the effects of a novel herb formula, Hepad, on PD. Dose-dependent treatment with 1-methyl-4-phenylpyridinium (MPP+) decreased the viability of SH-SY5Y cells, and Hepad inhibited the toxic effect of MPP+. Hepad blocked the production of reactive oxygen species (ROS) induced by MPP+ in SH-SY5Y cells, and suppressed the activation of caspase 9 and caspase 3 due to MPP+. A rat model of PD was generated by 6-hydroxydopamine (6-OHDA) injection into the left medial forebrain bundle (MFB) of SD rats. In D-amphetamine sulfate-induced rotational behavioral tests, Hepad administration attenuated circling behavior relative to the 6-OHDA-treated disease group. In addition, Hepad treatment significantly increased the tyrosine hydroxylase (TH)-positive cells in the substantia nigra pars compacta (SNpc) that had decreased in response to 6-OHDA treatment (P<0.05). OX-6 expression, which indicates the presence of microglial cells, decreased significantly after treatment of Hepad in contrast to the 6-OHDA-treated disease group (P<0.05). These results indicate that Hepad may be a useful neuroprotective material for the treatment of neurodegenerative disorders such as PD.

Parkinson’s disease (PD) is a common neurodegenerative disease characterized the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). Brain endogenous morphine biosynthesis was reported to be impaired in PD patients and exogenous morphine attenuated 6-hydroxydopamine (6-OHDA)-induced cell death in vitro. However, the mechanisms underlying neuroprotection of morphine in PD are still unclear. In the present study, we investigated the neuroprotective effects of low-dose morphine in cellular and animal models of PD and the possible underlying mechanisms. Herein, we found 6-OHDA and rotenone decreased the mRNA expression of key enzymes involved in endogenous morphine biosynthesis in SH-SY5Y cells. Incubation of morphine prevented 6-OHDA-induced apoptosis, restored mitochondrial membrane potential, and inhibited the accumulation of intracellular reactive oxygen species (ROS) in SH-SY5Y cells. Furthermore, morphine attenuated the 6-OHDA-induced endoplasmic reticulum (ER) stress possible by activating autophagy in SH-SY5Y cells. Finally, oral application of low-dose morphine significantly improved midbrain tyrosine hydroxylase (TH) expression, decreased apomorphine-evoked rotation and attenuated pain hypersensitivity in a 6-OHDA-induced PD rat model, without the risks associated with morphine addiction. Feeding of low-dose morphine prolonged the lifespan and improved the motor function in several transgenic Drosophila PD models in gender, genotype, and dose-dependent manners. Overall, our results suggest that neuroprotection of low-dose morphine may be mediated by attenuating ER stress and oxidative stress, activating autophagy, and ameliorating mitochondrial function.

Progressive loss in dopaminergic neurons (DA) of substantia nigra pars compacta (SNc) leads to Parkinson's disease with a hypothesis of oxidative stress generation. The present study was conducted to determine the long-term efficacy of silymarin (SM) post-treatment on 6-OHDA-induced oxidative stress in the SNc of male rats. Male Wistar rats were received 6-OHDA (8μg/rat) into SNc. After 3weeks, as recovery period, the animals were treated with i.p. injection of SM at different doses of 100, 200, or 300mg/kg for 15days. At the end of the treatment, motor function, neuronal cell count, antioxidant enzymes, and lipid peroxidation and tyrosine hydroxylase (TH) activities were evaluated in the ventral midbrain tissue. The 6-OHDA significantly decreased (p ≤ 0.05) motor function, antioxidant enzyme activity, GSH level, and GSH/GSSG ratio and caused an augmentation in GSSG and lipid peroxidation level. The 6-OHDA also reduced the population of neurons and TH expression. The SM repaired the 6-OHDA-induced motor impairment, antioxidant enzyme suppression, and TH down-regulation. All three doses of SM could restore the MDA level to the normal range in the 6-OHDA-lesioned rats and could reversed the effect of 6-OHDA on GSH, GSSG level, and GSH/GSSG ratio. The SM treatment significantly and dose-dependently increased (p ≤ 0.001) the total number of surviving neurons in the SNc. Silymarin chronic treatment restored the brain's antioxidant capacity and salvaged neurons from oxidative stress-induced neurodegeneration. The SM could also improve motor function in parkinsonian animals by increasing TH expression. These results recommend that application of SM over initial clinical stages may depict a hopeful approach versus PD. However, more research is needed to confirm this issue.

Parkinson disease (PD) is the second most common age-related neurodegenerative disease after Alzheimer disease, characterized by loss of dopaminergic neurons in substantia nigra pars compacta, accompanied by motor and non-motor symptoms. Idiopathic PD is the most common cause of Parkinsonism (primary Parkinsonism) while, certain medication and different groups of neurological disorder may be causes of secondary Parkinsonism. The presence of intraneuronal proteinaceous cytoplasmic inclusions “Lewy Bodies” and the loss of the nigrostriatal dopaminergic neurons are the main neuropathological hallmarks of PD. However, the etiology of the disease is still undefined; several studies assume that oxidative stress, mitochondrial defects, neuroinflammation, apoptosis and excitotoxicity play vital roles in the pathogenesis and progress of the disease. Experimental models of PD can be induced by several neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 6-hydroxydopamine, rotenone and paraquat which produce neuropathological and neurochemical changes that are identical to those seen in PD. The primary drug for PD treatment is L-dopa; however, drug-induced dyskinesia and motor complications restricted its use as long term treatment. Dopamine agonists are alternative options for initial treatment of PD and have been reported to retard the onset of motor complications. Combination of L-dopa with other medications, such ascatechol-O-methyltransferase inhibitors and monoamine oxidase B inhibitors has the ability to alleviate L-dopa-induced motor complications. Anticholinergic drugs can be used to control the symptoms of PD but their cognitive and autonomic side effects make them unsuitable for the elderly.

Dephosphorylation of Six2Y129 protects tyrosine hydroxylase-positive cells in SNpc by regulating TEA domain 1 expression

Parkinson disease (PD) is characterized by the selective demise of dopaminergic (DA) neurons in the substantial nigra pars compacta. Dysregulation of transcriptional factor myocyte enhancer factor 2D (MEF2D) has been implicated in the pathogenic process in in vivo and in vitro models of PD. Here, we identified a small molecule bis(3)-cognitin (B3C) as a potent activator of MEF2D. We showed that B3C attenuated the toxic effects of neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)) by activating MEF2D via multiple mechanisms. B3C significantly reduced MPP(+)-induced oxidative stress and potentiated Akt to down-regulate the activity of MEF2 inhibitor glycogen synthase kinase 3β (GSK3β) in a DA neuronal cell line SN4741. Furthermore, B3C effectively rescued MEF2D from MPP(+)-induced decline in both nucleic and mitochondrial compartments. B3C offered SN4741 cells potent protection against MPP(+)-induced apoptosis via MEF2D. Interestingly, B3C also protected SN4741 cells from wild type or mutant A53T α-synuclein-induced cytotoxicity. Using the in vivo PD model of C57BL/6 mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP), we showed that B3C maintained redox homeostasis, promoted Akt function activity, and restored MEF2D level in midbrain neurons. Moreover, B3C greatly prevented the loss of tyrosine hydroxylase signal in substantial nigra pars compacta DA neurons and ameliorated behavioral impairments in mice treated with MPTP. Collectedly, our studies identified B3C as a potent neuroprotective agent whose effectiveness relies on its ability to effectively up-regulate MEF2D in DA neurons against toxic stress in models of PD in vitro and in vivo.

Ellagic acid exerts protective effect in intrastriatal 6-hydroxydopamine rat model of Parkinson’s disease: Possible involvement of ERβ/Nrf2/HO-1 signaling

Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder characterized by the accumulation of accumulated alpha-synuclein (α-Syn) in substantia nigra. Research has shown that selenium (Se) can protect neural cells through the actions of selenoproteins, including selenoprotein P (SelP) and selenoprotein S (SelS), which participate in endoplasmic reticulum-associated protein degradation (ERAD). In this study, we investigated the potential protective role of Se in a pre-clinical PD rat model.We aimed to evaluate the therapeutic effects of Se administration in the 6-hydroxydopamine (6-OHDA) induced unilateral rat PD model. Male Wistar rats were utilised for unilateral PD animal model which were subjected to stereotaxic surgery and injected with 20 μg 6-OHDA/5 μl 0.2% ascorbate saline. After confirming the model, the rats were intraperitoneally injected with 0.1, 0.2, and 0.3 mg/kg of sodium selenite for 7 days. We then performed behavioral tests, including apomorphine-induced rotation, hanging, and rotarod tests. Following sacrifice, we analysed the substantia nigra area of the brain and serum for protein quantification, element analysis, and gene expression analysis.Our results indicate that the administration of 0.3 mg/kg of Se improved the motor deficiency in hanging, rotarod, and apomorphine-induced rotational tests. While there was no significant improvement in the expression of α-Syn, Se increased the expression of selenoproteins. Additionally, levels of selenoproteins, Se, and α-Syn both brain and serum were re-established by the treatment, suggesting the role of Se on the α-Syn accumulation. Furthermore, Se improved PD-induced biochemical deficits by increasing the levels of SelS and SelP (p<0.005).In conclusion, our findings suggest that Se may have a protective role in PD. 0.3 mg/kg dosage of Se increased the expression of selenoproteins, reduced the accumulation of α-Syn in the brain, and improved PD-induced motor deficits. These results suggest that Se may be a potential therapeutic option for PD treatment.