Correction to: Dietary Supplementation of Walnut Partially Reverses 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Induced Neurodegeneration in a Mouse Model of Parkinson’s Disease

Neurochemical Research - The original version of this article unfortunately contains an error in Fig. 2a (4th image for walnut). This has been corrected by publishing this erratum.     

Intragastric Administration of Casein Leads to Nigrostriatal Disease Progressed Accompanied with Persistent Nigrostriatal—Intestinal Inflammation Activited and Intestinal Microbiota—Metabolic Disorders Induced in MPTP Mouse Model of Parkinson’s Disease

Neurochemical Research - Gut microbial dysbiosis and alteration of gut microbiota composition in Parkinson's disease (PD) have been increasingly reported, no recognized therapies are available...     

Probucol Affords Neuroprotection in a 6-OHDA Mouse Model of Parkinson’s Disease

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic nigrostriatal neurons. Although the etiology of the majority of human PD cases is unknown, experimental evidence points to oxidative stress as an early and causal event. Probucol is a lipid-lowering phenolic compound with anti-inflammatory and antioxidant properties that has been recently reported as protective in neurotoxicity and neurodegeneration models. This study was designed to investigate the effects of probucol on the vulnerability of striatal dopaminergic neurons to oxidative stress in a PD in vivo model. Swiss mice were treated with probucol during 21 days (11.8 mg/kg; oral route). Two weeks after the beginning of treatment, mice received a single intracerebroventricular (i.c.v.) infusion of 6-hydroxydopamine (6-OHDA). On the 21st day, locomotor performance, striatal oxidative stress-related parameters, and striatal tyrosine hydroxylase and synaptophysin levels, were measured as outcomes of toxicity. 6-OHDA-infused mice showed hyperlocomotion and a significant decrease in striatal tyrosine hydroxylase (TH) and synaptophysin levels. In addition, 6-OHDA-infused mice showed reduced superoxide dismutase activity and increased lipid peroxidation and catalase activity in the striatum. Notably, probucol protected against 6-OHDA-induced hyperlocomotion and striatal lipid peroxidation, catalase upregulation and decrease of TH levels. Overall, the present results show that probucol protects against 6-OHDA-induced toxicity in mice. These findings may render probucol as a promising molecule for further pharmacological studies on the search for disease-modifying treatment in PD.     

Neurotherapeutic Effects of Bee Venom in a Rotenone-Induced Mouse Model of Parkinson’s Disease

Neurophysiology - Parkinson’s disease (PD) is a widespread progressive neurodegenerative disease; its main neuropathological hallmark is massive loss of dopaminergic neurons. Most PD studies...     

Mitochondria and Quality Control Defects in a Mouse Model of Gaucher Disease—Links to Parkinson’s Disease

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<Emphasis Type="Italic">Lycium barbarum</Emphasis> Polysaccharide Promotes Nigrostriatal Dopamine Function by Modulating PTEN/AKT/mTOR Pathway in a Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Murine Model of Parkinson’s Disease

To investigate the effects of Lycium barbarum polysaccharide (LBP) on pathological symptoms and behavioral deficits in a Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease (PD) mouse model. The therapeutic effects of LBP were monitored with an Open field test, a Rotarod test and a Morris water maze test. We also investigated the mechanisms with qRT-PCR and Western blotting analyses. After a relatively short-term LBP treatment, the total distance and walking time of PD mice significantly increased. The staying duration on the rod of PD mice increased in the Rotarod test. LBP can up-regulate levels of SOD2, CAT and GPX1 and inhibit the abnormal aggregation of α-synuclein induced by MPTP. LBP treatment can also up-regulate the phosphorylation of AKT and mTOR, and may play its protective role by activating the PTEN/AKT/mTOR signaling axis. These results suggest that LBP can effectively alleviate the degeneration in the nigrostriatal system induced by MPTP treatment. It may be a potential candidate for the treatment of Parkinson’s disease.     

Progranulin Gene Delivery Protects Dopaminergic Neurons in a Mouse Model of Parkinson’s Disease

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by tremor, rigidity and akinesia/bradykinesia resulting from the progressive loss of nigrostriatal dopaminergic neurons. To date, only symptomatic treatment is available for PD patients, with no effective means of slowing or stopping the progression of the disease. Progranulin (PGRN) is a 593 amino acid multifunction protein that is widely distributed throughout the CNS, localized primarily in neurons and microglia. PGRN has been demonstrated to be a potent regulator of neuroinflammation and also acts as an autocrine neurotrophic factor, important for long-term neuronal survival. Thus, enhancing PGRN expression may strengthen the cells resistance to disease. In the present study, we have used the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD to investigate the possible use of PGRN gene delivery as a therapy for the prevention or treatment of PD. Viral vector delivery of the PGRN gene was an effective means of elevating PGRN expression in nigrostriatal neurons. When PGRN expression was elevated in the SN_C, nigrostriatal neurons were protected from MPTP toxicity in mice, along with a preservation of striatal dopamine content and turnover. Further, protection of nigrostriatal neurons by PGRN gene therapy was accompanied by reductions in markers of MPTP-induced inflammation and apoptosis as well as a complete preservation of locomotor function. We conclude that PGRN gene therapy may have beneficial effects in the treatment of PD.     

NLRP3 Inflammasome Inhibitor Ameliorates Amyloid Pathology in a Mouse Model of Alzheimer’s Disease

The activation of the NLRP3 inflammasome signaling pathway plays an important role in the neuroinflammation in Alzheimer’s disease (AD). In this study, we investigated the effects of JC-124, a rationally designed NLRP3 inflammasome inhibitor, on AD-related deficits in CRND8 APP transgenic mice (TgCRND8). We first demonstrated increased formation and activation of NLRP3 inflammasome in TgCRND8 mice compared to non-transgenic littermate controls, which was inhibited by the treatment with JC-124. Importantly, JC-124 treatment led to decreased levels of Aβ deposition and decreased levels of soluble and insoluble Aβ_1–42 in the brain of CRND8 mice which was accompanied by reduced β-cleavage of APP, reduced activation of microglia but enhanced astrocytosis. Oxidative stress was decreased and synaptophysin was increased in the CRND8 mice after JC-124 treatment, demonstrating a neuroprotective effect. Overall, these data demonstrated beneficial effects of JC-124 as a specific NLRP3 inflammasome inhibitor in AD mouse model and supported the further development of NLRP3 inflammasome inhibitors as a viable option for AD therapeutics.     

Synaptic Protein Alterations in Parkinson’s Disease

Alterations occur within distal neuronal compartments, including axons and synapses, during the course of neurodegenerative diseases such as Parkinson’s disease (PD). These changes could hold important implications for the functioning of neural networks, especially since research studies have shown a loss of dendritic spines locating to medium spiny projection neurons and impaired axonal transport in PD-affected brains. However, despite ever-increasing awareness of the vulnerability of synapses and axons, inadequate understanding of the independent mechanisms regulating non-somatic neurodegeneration prevails. This has resulted in limited therapeutic strategies capable of targeting these distinct cellular compartments. Deregulated protein synthesis, folding and degrading proteins, and protein quality-control systems have repeatedly been linked with morphological and functional alterations of synapses in the PD-affected brains. Here, we review current understanding concerning the proteins involved in structural and functional changes that affect synaptic contact-points in PD. The collection of studies discussed emphasizes the need for developing therapeutics aimed at deregulated protein synthesis and degradation pathways operating at axonal and dendritic synapses for preserving “normal” circuitry and function, for as long as possible.     

Tauroursodeoxycholic Acid Prevents MPTP-Induced Dopaminergic Cell Death in a Mouse Model of Parkinson’s Disease

Mitochondrial dysfunction and oxidative stress are implicated in the neurodegenerative process in Parkinson??s disease (PD). Moreover, c-Jun N-terminal kinase (JNK) plays an important role in dopaminergic neuronal death in substantia nigra pars compacta. Tauroursodeoxycholic acid (TUDCA) acts as a mitochondrial stabilizer and anti-apoptotic agent in several models of neurodegenerative diseases. Here, we investigated the role of TUDCA in preventing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurodegeneration in a mouse model of PD. We evaluated whether TUDCA modulates MPTP-induced degeneration of dopaminergic neurons in the nigrostriatal axis, and if that can be explained by regulation of JNK phosphorylation, reactive oxygen species (ROS) production, glutathione S-transferase (GST) catalytic activation, and Akt signaling, using C57BL/6 glutathione S-transferase pi (GSTP) null mice. TUDCA efficiently protected against MPTP-induced dopaminergic degeneration. We have previously demonstrated that exacerbated JNK activation in GSTP null mice resulted in increased susceptibility to MPTP neurotoxicity. Interestingly, pre-treatment with TUDCA prevented MPTP-induced JNK phosphorylation in mouse midbrain and striatum. Moreover, the anti-oxidative role of TUDCA was demonstrated in vivo by impairment of ROS production in the presence of MPTP. Finally, results herein suggest that the survival pathway activated by TUDCA involves Akt signaling, including downstream Bad phosphorylation and NF-??B activation. We conclude that TUDCA is neuroprotective in an in vivo model of PD, acting mainly by modulation of JNK activity and cellular redox thresholds, together with activation of the Akt pro-survival pathway. These results open new perspectives for the pharmacological use of TUDCA, as a modulator of neurodegeneration in PD.     

Lack of long-term changes in circadian,locomotor, and cognitive functions in acute and chronic MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse models of parkinson’s disease

In addition to the hallmark motor disorders in Parkinson’s disease (PD) patients, nonmotor symptoms have attracted increasing attention. Among the nonmotor symptoms, sleep disturbances and cognitive deficits are frequently reported and contribute to a decrease in the quality of life. The pathophysiology of cognitive and sleep-wake abnormalities in PD is poorly understood partially due to the lack of appropriate animal models that fully replicate the entire pathological and behavioral spectrum of the disease. In this study, we undertook a long-term evaluation of circadian, locomotor and cognitive abilities in both acute and chronic MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated mouse models. Activity rhythms and locomotor activity were assayed under light-dark cycles, constant darkness, or constant light, re-entrainment to shifts of the light-dark cycle, and a behavioral masking paradigm. Cognitive abilities were assessed using a radial water maze task. Although both acute and chronic treatment regimes induced 70% degeneration of dopaminergic neurons in the substantia nigra, neither circadian nor cognitive alterations were observed even after nearly 1?yr. During aging, there was a significant decrease of locomotor activity and of several circadian parameters without any exacerbation in MPTP-treated animals. These results emphasize the limitations of the MPTP-treated mouse as an animal model of nonmotor symptoms of PD in addition to the already well-documented inadequacy to replicate cardinal motor features of the disease.     

Brain Gene Expression of a Sporadic (icv-STZ Mouse) and a Familial Mouse Model (3xTg-AD Mouse) of Alzheimer’s Disease

Alzheimer’s disease (AD) can be divided into sporadic AD (SAD) and familial AD (FAD). Most AD cases are sporadic and may result from multiple etiologic factors, including environmental, genetic and metabolic factors, whereas FAD is caused by mutations of presenilins or amyloid-β (Aβ) precursor protein (APP). A commonly used mouse model for AD is 3xTg-AD mouse, which is generated by over-expression of mutated presenilin 1, APP and tau in the brain and thus represents a mouse model of FAD. A mouse model generated by intracerebroventricular (icv) administration of streptozocin (STZ), icv-STZ mouse, shows many aspects of SAD. Despite the wide use of these two models for AD research, differences in gene expression between them are not known. Here, we compared the expression of 84 AD-related genes in the hippocampus and the cerebral cortex between icv-STZ mice and 3xTg-AD mice using a custom-designed qPCR array. These genes are involved in APP processing, tau/cytoskeleton, synapse function, apoptosis and autophagy, AD-related protein kinases, glucose metabolism, insulin signaling, and mTOR pathway. We found altered expression of around 20 genes in both mouse models, which affected each of above categories. Many of these gene alterations were consistent with what was observed in AD brain previously. The expression of most of these altered genes was decreased or tended to be decreased in the hippocampus of both mouse models. Significant diversity in gene expression was found in the cerebral cortex between these two AD mouse models. More genes related to synaptic function were dysregulated in the 3xTg-AD mice, whereas more genes related to insulin signaling and glucose metabolism were down-regulated in the icv-STZ mice. The present study provides important fundamental knowledge of these two AD mouse models and will help guide future studies using these two mouse models for the development of AD drugs.     

Loss of Collapsin Response Mediator Protein 4 Attenuates 6-Hydroxydopamine-Induced Impairments in a Mouse Model of Parkinson’s Disease

Neurochemical Research - Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by impaired motor symptoms induced by the degeneration of dopaminergic neurons of the...     

ATF6alpha Promotes Astroglial Activation and Neuronal Survival in a Chronic Mouse Model of Parkinson’s Disease

Accumulating evidence suggests a crucial role for the unfolded protein response (UPR) in Parkinson’s disease (PD). In this study, we investigated the relevance of the UPR in a mouse model of chronic MPTP/probenecid (MPTP/P) injection, which causes severe and persistent degeneration of dopaminergic neurons. Enhanced activation of the UPR branches, including ATF6α and PERK/eIF2α/ATF4, was observed after MPTP/P injections into mice. Deletion of the ATF6α gene accelerated neuronal degeneration and ubiquitin accumulation relatively early in the MPTP/P injection course. Surprisingly, astroglial activation was strongly suppressed, and production of the brain-derived neurotrophic factor (BDNF) and anti-oxidative genes, such as heme oxygenase-1 (HO-1) and xCT, in astrocytes were reduced in ATF6α −/− mice after MPTP/P injections. Decreased BDNF expression in ATF6α −/− mice was associated with decreased expression of GRP78, an ATF6α-dependent molecular chaperone in the ER. Decreased HO-1 and xCT levels were associated with decreased expression of the ATF4-dependent pro-apoptotic gene CHOP. Consistent with these results, administration of the UPR-activating reagent tangeretin (5,6,7,8,4′-pentamethoxyflavone; IN19) into mice enhanced the expression of UPR-target genes in both dopaminergic neurons and astrocytes, and promoted neuronal survival after MPTP/P injections. These results suggest that the UPR is activated in a mouse model of chronic MPTP/P injection, and contributes to the survival of nigrostriatal dopaminergic neurons, in part, through activated astrocytes.     

2′,3′-Dideoxycytidine Protects Dopaminergic Neurons in a Mouse Model of Parkinson’s Disease

DNA polymerase-β (DNA pol-β) plays a crucial role in the pathogenesis of Parkinson’s disease (PD). The aim of this study was to investigate the neuroprotective effects of a DNA polymerase-β inhibitor 2′,3′-dideoxycytidine (DDC) in PD models. In the in vitro studies, primary cultured neurons were challenged with 1-methyl-4-phenylpyridinium ion (MPP⁺). The expression of DNA pol-β was assessed using western blot. The neuroprotective effect of DNA pol-β knockdown and DNA pol-β inhibitor DDC was determined using cell viability assay and caspase-3 activity assay. We found that MPP⁺ induced neuronal death and the activation of caspase-3 in a dose-dependent manner. The expression of DNA pol-β increased after the neurons were exposed to MPP⁺. DNA pol-β siRNA or DNA pol-β inhibitor DDC attenuated neuronal death induced by MPP⁺. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD, MPTP treatment triggered behavioral deficits and nigrostriatal lesions. Pretreatment with DDC attenuated MPTP-induced behavioral deficits, dopaminergic neuronal death and striatal dopamine depletion in the MPTP mouse model. These results indicate that DNA pol-β inhibitors may present a novel promising therapeutic option for the neuroprotective treatment of PD.