Apomorphine-induced Rotation Research Articles

Acylated Ghrelin is Protective Against 6-OHDA-induced Neurotoxicity by Regulating Autophagic Flux.

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, and our previous study revealed that autophagic flux dysfunction contributes to the neuron death in 6-OHDA-induced PD models. Acylated ghrelin is a neuropeptide that has a variety of actions in the central nervous system. In the current study, we aimed to investigate whether ghrelin is neuroprotective in 6-OHDA-induced rat model and SH-SY5Y cell model and whether it is related to autophagic flux regulation. We observed that ghrelin could effectively reduce apomorphine-induced contralateral rotation in 6-OHDA-induced PD rats, preserve the expression of tyrosine hydroxylase (TH) and increase the cell viability. It could upregulate the expression of autophagy related proteins like Atg7 and LC3-II and downregulate p62, and downregulate apoptosis related proteins like bax and cleaved caspase 3. SH-SY5Y cells transfected with adenovirus Ad-mCherry-GFP-LC3B further revealed that ghrelin could relieve the autophagic flux dysfunction induced by 6-OHDA. Lysotracker staining showed that ghrelin could reverse the decrease in lysosomes induced by 6-OHDA and immunofluorescence staining revealed a reverse of TFEB level in SH-SY5Y cells. Blocking autophagy activation with 3-methyladenine (3-MA) in rats treated with ghrelin and 6-OHDA showed no notable change in apoptosis-related markers, while blocking autophagosome fusion with lysosomes with chloroquine could notably reverse the downregulation of bax/bcl-2 ratio and cleaved caspase three expression by ghrelin. Additionally, knockdown ATG7, the upstream regulator of autophagy, with siRNA could further decrease the number of apoptotic cells in SH-SY5Y cells exposed to 6-OHDA and treated with ghrelin, while knockdown TFEB, a key transcription factor for lysosome biosynthesis and function, with siRNA could completely abolish the anti-apoptosis effect of ghrelin. These data suggest that ghrelin is neuroprotective in 6-OHDA-induced PD models via improving autophagic flux dysfunction and restoration of TFEB level.

Therapeutic Potential of Magnetic Nanoparticle-Based Human Adipose-Derived Stem Cells in a Mouse Model of Parkinson's Disease.

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra. Several treatments for PD have focused on the management of physical symptoms using dopaminergic agents. However, these treatments induce various adverse effects, including hallucinations and cognitive impairment, owing to non-targeted brain delivery, while alleviating motor symptoms. Furthermore, these therapies are not considered ultimate cures owing to limited brain self-repair and regeneration abilities. In the present study, we aimed to investigate the therapeutic potential of human adipose-derived stem cells (hASCs) using magnetic nanoparticles in a 6-hydroxydopamine (6-OHDA)-induced PD mouse model. We used the Maestro imaging system and magnetic resonance imaging (MRI) for in vivo tracking after transplantation of magnetic nanoparticle-loaded hASCs to the PD mouse model. The Maestro imaging system revealed strong hASCs signals in the brains of PD model mice. In particular, MRI revealed hASCs distribution in the substantia nigra of hASCs-injected PD mice. Behavioral evaluations, including apomorphine-induced rotation and rotarod performance, were significantly recovered in hASCs-injected 6-OHDA induced PD mice when compared with saline-treated counterparts. Herein, we investigated whether hASCs transplantation using magnetic nanoparticles recovered motor functions through targeted brain distribution in a 6-OHDA induced PD mice. These results indicate that magnetic nanoparticle-based hASCs transplantation could be a potential therapeutic strategy in PD.

Beneficial Effect of Melatonin on Motor and Memory Disturbances in 6-OHDA-Lesioned Rats.

Previous evidence has shown a link between neurodegenerative diseases, including Parkinson's disease (PD), and melatonin. The data in the literature about the impact of the hormone under different experimental PD conditions are quite controversial, and its effect on memory impairment in the disease is very poorly explored. The current research was aimed at investigating the role of melatonin pretreatment on memory and motor behavior in healthy rats and those with the partial 6-hydroxydopamine (6-OHDA) model of PD. All rodents were pretreated with melatonin (20mg/kg, intraperitoneally) for 5days. At 24h and 7days after the first treatment for healthy rats, and at the second and third week post-lesion for those with PD, the animals were tested behaviorally (apomorphine-induced rotations, rotarod, and passive avoidance tests). The neurochemical levels of dopamine (DA), acetylcholine (ACh), noradrenaline (NA), and serotonin (Sero) in the brain were also determined. The results showed that in healthy animals, melatonin pretreatment had amnestic and motor-suppressive effects and did not change the levels of measured brain neurotransmitters. In animals with PD, melatonin pretreatment exerted a neuroprotective effect, manifested as a significantly decreased number of apomorphine-induced rotations, reduced number of falls in the rotarod test, and improved memory performance. The brain DA and ACh concentrations in the same animals were restored to the control levels, and those of NA and Sero did not change. Our results demonstrate a beneficial effect of melatonin on memory and motor disturbance in 6-OHDA-lesioned rats.

Paeonol Protection Against Intrastriatal 6-Hydroxydopamine Rat Model of Parkinson's Disease.

Introduction:Parkinson’s Disease (PD) presentations comprise frequent movement disorders in the elderly with various symptoms consisting of motor and non-motor complications. Paeonol is a phenolic chemical agent that has shown antioxidant and anti-inflammatory effects in different disorders and promising effects on metabotropic glutamate receptors (mGluR)- and GABAA-mediated neurotransmission. In this research, we tried to show the neuroprotective potential of paeonol in rat PD model induced by intrastriatal 6-hydroxydopamine (6-OHDA).Methods:Rats with intrastriatal 6-OHDA lesioning received with paeonol at a dosage of 100 mg/kg/d for one week. In the end, some biomarkers of oxidative stress, apoptosis, and astrogliosis in nigral and striatal tissues were evaluated in addition to behavioral and Tyrosine Hydroxylase (TH) immunohistochemical analysis.Results:The obtained data showed that paeonol alleviates apomorphine-induced rotations and reduces the delay time to initiate and the total time in the narrow beam test. However, its beneficial behavioral effect vanished after intracerebroventricular administration of mGluR III or GABAA receptor antagonists. Moreover, paeonol significantly restored striatal malondialdehyde, tissue levels of reactive oxygen species, the activity of the protective and vital enzymes consisting of superoxide dismutase and catalase, Glial Fibrillary Acidic Protein (GFAP), DNA fragmentation, phosphor apoptosis signal-regulating kinase 1, and nigral aquaporin 4 with no significant and proper change of nitrite, interleukin-1β, inducible nitric oxide synthase, and angiotensin II. Additionally, paeonol prevented injury and reduced tyrosine hydroxylase-containing neurons in the midbrain nigral tissue.Conclusion:These obtained findings evidently designate neuroprotective property of paeonol in 6-OHDA murine model of PD that is exerted via easing of oxidative stress, apoptosis, astrogliosis, and its advantageous effect is to some extent mediated via mGluR III/GABAA pathway.

Chronic feeding with 3% dried raw blueberries (V. corymbosum) reduces apomorphine-induced rotations and striatal dopaminergic loss in hemiparkinsonian rats

Blueberries (BB) are rich in antioxidant polyphenols, and their intake could prevent Parkinson’s disease (PD). Here we assessed whether rats chronically fed dried raw BB develop resistance to dopaminergic denervation and motor disorders caused by unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA), a dopaminergic neurotoxin acting mainly by inducing oxidative stress. Male rats were fed either with LabDiet® alone or supplemented with 3% lyophilized raw BB for 2 weeks before and 3 weeks after injecting 6-OHDA (day 0) or vehicle (mock lesion) into the right striatum. The cylinder test was performed on days −14, −7, −1, +7, +14, and +21; the percentage of ipsilateral forepaw (IF) use asymmetry was determined by counting the wall contacts made with either forepaw or with both. Apomorphine (0.25 mg/kg, s.c.)-induced rotation was performed on days −1, +7, +14, and +21. Full contralateral rotations were counted in 3-min periods, every 15 min, up to 90 min. Striatal slices were immunostained for tyrosine hydroxylase (TH) and the ionized calcium-binding protein-1 adapter (Iba1) [immunoreactive area or microglia count in right striatum expressed as % of the left striatum]. Antioxidants in BB methanolic extracts neutralized the free radical 2,2-diphenyl-1-picrylhydrazyl in a concentration-dependent manner. Anthocyanins have been reported as the most abundant polyphenols in BB. Using the pH differential method, the total anthocyanin content (malvidin-3-glucoside equivalents) in raw BB averaged 21.04 mg/g dry weight. The range of anthocyanin intake by rats throughout the study varied from 37.7 to 72.2 mg/kg body weight. The time and food type factors, as well as their interaction were significant according to two-way RM-ANOVA in both the apomorphine-induced rotations and the cylinder test. Compared with LabDiet® alone, chronic supplementation with 3% dried raw BB decreased apomorphine-induced rotations on days +14 and +21 (p < 0.001) and produced a 46% reduction in total rotations post-surgery (p < 0.05), but only caused a partial, non-significant, decrease of IF asymmetry. BB supplementation reduced TH loss in the striatum (p < 0.05) but did not attenuate the increase of Iba1+ microglia. The consumption of 3% dried raw blueberries attenuates dopaminergic denervation and partially reverses motor disorders in the 6-OHDA-induced PD model in rats. The phytochemicals of raw blueberries that contribute to the observed neuroprotective effect are yet to be identified.

Histamine-4 receptor antagonist ameliorates Parkinson-like pathology in the striatum

Growing evidence indicates that microglia activation and a neuroinflammatory trigger contribute to dopaminergic cell loss in Parkinson’s disease (PD). Furthermore, increased density of histaminergic fibers and enhanced histamine levels have been observed in the substantia nigra of PD-postmortem brains. Histamine-induced microglial activation is mediated by the histamine-4 receptor (H4R). In the current study, gene set enrichment and pathway analyses of a PD basal ganglia RNA-sequencing dataset revealed that upregulation of H4R was in the top functional category for PD treatment targets. Interestingly, the H4R antagonist JNJ7777120 normalized the number of nigrostriatal dopaminergic fibers and striatal dopamine levels in a rotenone-induced PD rat model. These improvements were accompanied by a reduction of α-synuclein-positive inclusions in the striatum. In addition, intracerebroventricular infusion of JNJ7777120 alleviated the morphological changes in Iba-1-positive microglia and resulted in a lower tumor necrosis factor-α release from this brain region, as well as in ameliorated apomorphine-induced rotation behaviour. Finally, JNJ7777120 also restored basal ganglia function by decreasing the levels of γ-aminobutyric acid (GABA) and the 5-hydroxyindoleactic acid to serotonin (5-HIAA/5-HT) concentration ratios in the striatum of the PD model. Our results highlight H4R inhibition in microglia as a promising and specific therapeutic target to reduce or prevent neuroinflammation, and as such the development of PD pathology.

Neural Transplants From Human Induced Pluripotent Stem Cells Rescue the Pathology and Behavioral Defects in a Rodent Model of Huntington's Disease.

Huntington’s disease (HD) is a devastating, autosomal-dominant inheritance disorder with the progressive loss of medium spiny neurons (MSNs) and corticostriatal connections in the brain. Cell replacement therapy has been proposed as a potential therapeutic strategy to treat HD. Among various types of stem cells, human-induced pluripotent stem cells (iPSCs) have received special attention to develop disease modeling and cell therapy for HD. In the present study, the therapeutic effects of neural precursor cells (NPCs) derived from a human iPSC line (1231A3-NPCs) were investigated in the quinolinic acid (QA)-lesioned rat model of HD. 1231A3-NPCs were transplanted into the ipsilateral striatum 1 week after QA lesioning, and the transplanted animals showed significant behavioral improvements for up to 12 weeks based on the staircase, rotarod, stepping, apomorphine-induced rotation, and cylinder tests. Transplanted 1231A3-NPCs also partially replaced the lost neurons, enhanced endogenous neurogenesis, reduced inflammatory responses, and reconstituted the damaged neuronal connections. Taken together, these results strongly indicate that NPCs derived from iPSCs can potentially be useful to treat HD in the future.

Fraternine, a Novel Wasp Peptide, Protects against Motor Impairments in 6-OHDA Model of Parkinsonism.

Parkinson’s disease (PD) is a progressive neurodegenerative condition that affects the Central Nervous System (CNS). Insect venoms show high molecular variability and selectivity in the CNS of mammals and present potential for the development of new drugs for the treatment of PD. In this study, we isolated and identified a component of the venom of the social wasp Parachartergus fraternus and evaluated its neuroprotective activity in the murine model of PD. For this purpose, the venom was filtered and separated through HPLC; fractions were analyzed through mass spectrometry and the active fraction was identified as a novel peptide, called Fraternine. We performed two behavioral tests to evaluate motor discoordination, as well as an apomorphine-induced rotation test. We also conducted an immunohistochemical assay to assess protection in TH+ neurons in the Substantia Nigra (SN) region. Group treated with 10 μg/animal of Fraternine remained longer in the rotarod compared to the lesioned group. In the apomorphine test, Fraternine decreased the number of rotations between treatments. This dose also inhibited dopaminergic neuronal loss, as indicated by immunohistochemical analysis. This study identified a novel peptide able to prevent the death of dopaminergic neurons of the SN and recover motor deficit in a 6-OHDA-induced murine model of PD.

Exercise-Induced Neuroprotection in the 6-Hydroxydopamine Parkinson's Disease Model.

Exercise exerts helpful effects in Parkinson's disease. In this study, the 6-hydroxydopamine (6-OHDA) injection was used to investigate the effect of exercise on apomorphine-induced rotation and neurorestoration. Rats (n = 32) were divided into four groups: (1) Saline+Noexercise (Sham); (2) 6-OHDA+Noexercise (6-OHDA); (3) Saline+Exercise (S+EXE), and (4) 6-OHDA+Exercise (6-OHDA+EXE). The rats were administered 8μg 6-OHDA by injection into the right medial forebrain bundle. After 2weeks, the exercise group was run (14 consecutive days, 30min per day). One month after the surgery, following the injection of apomorphine, the 6-OHDA group displayed a significant increase in rotation and the 6-OHDA+EXE group showed a significant reduction of rotational asymmetry (P<0.001). 6-OHDA injection reduced the mRNA and protein expression of the AMP-activated protein kinase, brain-derived neurotropic factor, and tyrosine hydroxylase in relation to the Sham group and exercise increased these levels. Expression of the silent information regulator 2 homolog 1 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha was unexpectedly enhanced in the 6-OHDA groups in relation to the Sham group. These findings suggest that the 6-OHDA injection increased the neurodegeneration and mitochondrial and behavioral dysfunctions and the treadmill running attenuated these disorders in the ipsilateral striatum of the 6-OHDA+EXE group.

Intracerebral transplantation of HLA-homozygous human iPSC-derived neural precursors ameliorates the behavioural and pathological deficits in a rodent model of ischaemic stroke.

ObjectivesHuman‐induced pluripotent stem cells (hiPSCs) are a promising cell source for treating ischaemic stroke. Although autologous hiPSCs provide the advantage of avoiding immune rejection, their practical limitations, such as substantial amount of time and costs to generate individual iPSC lines, have hampered their widespread application in clinical settings. In this study, we investigated the therapeutic potential of neural precursor cells derived from human HLA‐homozygous induced pluripotent stem cells (hiPSC‐NPCs) following intracerebral transplantation into a rodent model of middle cerebral artery occlusion (MCAo).Materials and MethodsWe differentiated a GMP‐grade HLA‐homozygous hiPSC line (CMC‐hiPSC‐004) into neural precursor cells for transplantation into rats at the subacute stage of ischaemic stroke (ie at 7 days after the induction of MCAo). To investigate functional recovery, the transplanted animals were subjected to five behavioural tests, namely the rotarod, stepping, mNSS, staircase and apomorphine‐induced rotation tests, for up to 12 weeks, followed by histological analyses.ResultsWe observed that the hiPSC‐NPC transplantation produced significant behavioural improvements. At 12 weeks post‐transplantation, a high proportion of transplanted cells survived and had differentiated into MAP2+ mature neurons, GABAergic neurons and DARPP32+ medium spiny neurons. The transplanted cells formed neuronal connections with striatal neurons in the host brain. In addition, hiPSC‐NPC transplantation gave rise to enhanced endogenous repair processes, including decreases of post‐stroke neuroinflammation and glial scar formation and an increase of proliferating endogenous neural stem cells in the subventricular zone as well as the perilesional capillary networks.ConclusionsThese results strongly suggest that HLA‐homozygous hiPSC‐NPCs may be useful for treating ischaemic stroke patients.

Kolaviron protects against nigrostriatal degeneration and gut oxidative damage in a stereotaxic rotenone model of Parkinson's disease.

The asymptomatic and clinical stages of Parkinson's disease (PD) are associated with comorbid non-motor symptoms including gastrointestinal (GI) dysfunction. Although the neuroprotective and gastroprotective roles of kolaviron (KV) have been reported independently, whether KV-mediated GI-protective capacity could be beneficial in PD is unknown. We therefore investigated the modulatory effects of KV on the loss of dopaminergic neurons, locomotor abnormalities, and ileal oxidative damage when rats are lesioned in the nigrostriatal pathway. KV treatment markedly suppressed the behavioral deficit and apomorphine-induced rotations associated with rotenone lesioning. KV attenuated the loss of nigrostriatal dopaminergic neurons and perturbations in the striatal glucose-regulated protein (GRP78) and X-box binding protein 1 (XBP1) levels. Ileal epithelial injury following stereotaxic rotenone infusion was associated with oxidative stress and marked inhibition of acetylcholine esterase activity and reduced expression of occludin in the crypt and villi. While KV treatment attenuated the redox imbalance in the gut and enhanced occludin immunoreactivity, acetylcholinesterase activity was not affected. Our data demonstrate ileal oxidative damage as a characteristic non-motor gut dysfunction in PD while showing the potential dual efficacy of KV in the attenuation of both neural defects and gut abnormalities associated with PD.

Implantation of glial cell line-derived neurotrophic factor-expressing adipose tissue-derived stromal cells in a rat Parkinson’s disease model

ABSTRACT In previous studies, the effects of glial cell line-derived neurotrophic factor (GDNF) expressing adipose tissue-derived stromal cells (ADSCs) on Parkinson’s disease (PD) models have been studied but have not been elucidated. The present study aims to investigate this phenomenon and trace their differentiation in vivo. In our study, ADSCs were harvested from adult Sprague-Dawley rats, then genetically modified into GDNF-expressing system by lentivirus. The secretion of GDNF from the transduced cells was titrated by enzyme-linked immunosorbent assay (ELISA). Cellular differentiation in vitro was observed after induction. To examine survival and differentiation in vivo, they were injected into the striatum of 6-hydroxydopamine-lesioned rats, whose apomorphine-induced rotations were examined 2, 7, 14 and 21d after grafting. It’s found that GDNF-expressing ADSCs can differentiate into neuron-like cells in vitro. Moreover, engrafted GDNF-expressing ADSCs survived at least 90 days post-grafting and differentiated into dopaminergic neuron-like cells. Most importantly, these cells drastically improved the clinical symptoms of PD rats. In conclusion, ADSCs can be efficiently engineered by lentivirus system and deliver a therapeutic level of the transgene to target tissues. GDNF-ADSCs can improve behavior phenotype in the rat PD model. Moreover, ADSCs is a more readily available source of dopaminergic neurons, though a more effective procedure needs to be developed to enrich the number of differentiation.

Effects of Heating-needle Stimulation in Restoration of Weakened Descending Inhibition of Nociception in a Rat Model of Parkinson’s Disease

Here we investigated variations of endogenous descending modulation of nociception and therapeutic effects of intramuscular (i.m.) heating-needle stimulation in early stage of Parkinson’s disease (PD) induced by unilateral microinjection of 3.5 μl of 2.5 μg/μl 6-hydroxydopamine into the rat striatum. Paw withdrawal reflexes to noxious mechanical and heat stimuli in PD rats with and without exposure to i.m. 5.8% saline induced muscle nociception were evaluated. Experimental PD had no influence on mechanical or heat sensitivity in the baseline condition, whereas descending facilitation was stronger and descending inhibition was weaker in PD rats than vehicle-treated or naive rats during muscle nociception (P < 0.05). Striatal administration of 5 μg of dopamine failed to reverse the PD-associated changes in descending facilitation or inhibition, whereas dopamine in the thalamic mediodorsal (MD) nucleus and ventromedial (VM) nucleus significantly decreased the increase in descending facilitation and reversed the attenuation in descending inhibition, respectively (P < 0.05). I.m. 43 °C of heating-needle stimulation had no effects on the enhanced descending facilitation in PD rats, but it markedly increased descending inhibition and reversed the increase in the number of apomorphine-induced body rotations (P < 0.05), which effects were dose-dependently attenuated by raclopride, a dopamine 2 receptor antagonist, in the thalamic VM nucleus (P < 0.05). The results indicate that the early-stage PD is associated with enhanced descending facilitation and weakened descending inhibition. From clinical perspective, 43 °C heat therapeutic regime promises to selectively enhance descending inhibition that is accompanied by improvement of motor dysfunction in PD.

Repeated intrastriatal application of botulinum neurotoxin-A did not influence choline acetyltransferase-immunoreactive interneurons in hemiparkinsonian rat brain – A histological, stereological and correlational analysis

In Parkinson’s disease, dopamine depletion leads to hyperactivity of cholinergic interneurons in the caudate-putamen (CPu). Botulinum neurotoxin-A (BoNT-A) inhibits the release of acetylcholine in the peripheral nervous system and is also thought to act as a local anticholinergic drug when injected intrastriatally. In hemiparkinsonian (hemi-PD) rats, a unilateral intrastriatal injection of 1 ng BoNT-A significantly diminished apomorphine-induced rotation behavior for at least 3 months, the effect fading thereafter. A second intrastriatal BoNT-A application, 6 months after the first one, led to a stronger and longer-lasting, beneficial behavioral reaction.As a single BoNT-A injection was not cytotoxic in the rat striatum and resembled BoNT-A treatment in clinical practice, here, we investigated the structural outcome of repeated intrastriatal BoNT-A injections with respect to striatal volume, the number of choline acetyltransferase-immunoreactive (ChAT-ir) interneurons and of the length of their dendritic arbors, and the numeric density of ChAT-ir BoNT-A-induced varicosities (BiVs). Repeated unilateral intrastriatal BoNT-A application decreased the volume of the injected CPu, but did not significantly change the number of striatal ChAT-ir interneurons. Also, the total dendrite length of ChAT-ir interneurons after repeated BoNT-A application resembled the values in double vehicle-injected hemi-PD rats. In repeatedly BoNT-A-injected hemi-PD rats, the numeric density of ChAT-ir BiVs in the CPu was increased compared with rats only intrastriatally injected once with BoNT-A. Even repeated BoNT-A injections in rat striata did not cause substantial morphological changes in ChAT-ir neuron, except for the increased numeric density of ChAT-ir BiVs.

Intracerebral Transplantation of BDNF-overexpressing Human Neural Stem Cells (HB1.F3.BDNF) Promotes Migration, Differentiation and Functional Recovery in a Rodent Model of Huntington's Disease.

Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder caused by abnormally expanded CAG repeats in the huntingtin gene. The huntingtin gene mutation leads to the progressive degeneration of striatal GABAergic medium spiny neurons (MSN) and reduces the level of brain-derived neurotrophic factor (BDNF) in HD patient’s brain. BDNF is an essential neurotrophic factor for the cortico-striatal synaptic activity and the survival of GABAergic neurons. In this study, we transplanted BDNF-overexpressing human neural stem cells (HB1.F3.BDNF) into the contra-lateral side of unilateral quinolinic acid (QA)-lesioned striatum of HD rat model. The results of in vivo transplantation were monitored using various behavioral tests, 4.7 T animal magnetic resonance imaging (MRI) and immunohistochemical staining. We observed that the QA-lesioned rats receiving HB1.F3.BDNF cells exhibited significant behavioral improvements in the stepping, rotarod and apomorphine-induced rotation tests. Interestingly, contralaterally transplanted cells were migrated to the QA-lesioned striatum and the size of lateral ventricle was reduced. Histological analyses further revealed that the transplanted cells, which had migrated to the QA lesion site, were differentiated into the cells of GABAergic, MSN-type neurons expressing DARPP-32, and neural networks were established between the transplanted cells and the host brain, as revealed by retrograde tracing. Finally, there was a significant reduction of inflammatory response in HB1.F3.BDNF-transplanted HD animal model, compared with vehicle-transplanted group. Taken together, these results suggest that HB1.F3.BDNF can be an effective therapeutic strategy to treat HD patients in the future.

Exosomes derived from mesenchymal stem cells repair a Parkinson\u2019s disease model by inducing autophagy

Parkinson’s disease (PD) is a progressively debilitating neurodegenerative condition that leads to motor and cognitive dysfunction. At present, clinical treatment can only improve symptoms, but cannot effectively protect dopaminergic neurons. Several reports have demonstrated that human umbilical cord mesenchymal stem cells (hucMSCs) afford neuroprotection, while their application is limited because of their uncontrollable differentiation and other reasons. Stem cells communicate with cells through secreted exosomes (Exos), the present study aimed to explore whether Exos secreted by hucMSCs could function instead of hucMSCs. hucMSCs were successfully isolated and characterized, and shown to contribute to 6-hydroxydopamine (6-OHDA)-stimulated SH-SY5Y cell proliferation; hucMSC-derived Exos were also involved in this process. The Exos were purified and identified, and then labeled with PKH 26, it was found that the Exos could be efficiently taken up by SH-SY5Y cells after 12 h of incubation. Pretreatment with Exos promoted 6-OHDA-stimulated SH-SY5Y cells to proliferate and inhibited apoptosis by inducing autophagy. Furthermore, Exos reached the substantia nigra through the blood–brain barrier (BBB) in vivo, relieved apomorphine-induced asymmetric rotation, reduced substantia nigra dopaminergic neuron loss and apoptosis, and upregulated the level of dopamine in the striatum. These results demonstrate that hucMSCs-Exos have a treatment capability for PD and can traverse the BBB, indicating their potential for the effective treatment of PD.

Neuroprotective effect of regular swimming exercise on calretinin-positive striatal neurons of Parkinsonian rats.

In Parkinson's disease (PD), physical therapy is one of the mainstays of supportive treatment modalities. This study focused on the neuroprotective effect of regular exercise on striatal calretinin positive interneurons in a rat model of PD. 6-hydroxydopamine (6-OHDA) was injected unilaterally into the medial forebrain bundle of Wistar rats. 6-OHDA lesioned (Parkinsonian) and unlesioned (control) rats were divided into sedentary and exercise groups. Exercise groups had daily swimming sessions for 30min for 6 weeks. After 6-OHDA injections, an apomorphine-induced rotation test was performed (0.05mg/kg, subcutaneous) at the 3rd and 6th weeks. At the end of the 6th week, brains were removed following transcardiac perfusion. The brain sections were stained immunohistochemically for tyrosine hydroxylase and calretinin reactivity. The number of rotations was significantly lower in Parkinsonian exercise group compared to Parkinsonian sedentary group at the 6th week (p = 0.024) and there was significant difference between Parkisonian sedentary groups at the 3rd and 6th weeks (p < 0.002). The calretinin positive interneurons significantly increased in the Parkinsonian exercise group compared to Parkinsonian sedentary group (p = 0.0003) and control exercise group (p < 0.0001). To conclude, the swimming exercise led to a striking increment of calretinin positive interneurons in the striatum of Parkinsonian rat. These findings indicated that the neuroprotective mechanism of exercise increased the number of striatal calretinin positive interneurons that might generate new approaches for the mechanism of neuroprotection. We concluded that striatal calretinin positive interneurons have an important role in the neuroprotective mechanisms of exercise in PD.

Early transcranial direct current stimulation treatment exerts neuroprotective effects on 6-OHDA-induced Parkinsonism in rats

BackgroundTranscranial direct current stimulation (tDCS) has been proven to be able to modulate motor cortical plasticity might have potential as an alternative, adjunctive therapy for Parkinson’s disease (PD). However, the efficacy of tDCS in PD is still uncertain. A disease animal model may be useful to clarify the existence of a treatment effect and to explore an effective therapeutic strategy using tDCS protocols. ObjectiveThe current study was designed to identify the comprehensive therapeutic effects of tDCS in 6-hydroxydopamine (6-OHDA)-lesioned PD rats. MethodsFollowing early and long-term tDCS application (starting 24 h after PD lesion, 300 μA anodal tDCS, 20 min/day, 5 days/week) in awake PD animals for a total of 4 weeks, the effects of tDCS on motor and non-motor behaviors as well as dopaminergic neuron degeneration levels, were identified. ResultsWe found that the 4-week tDCS intervention significantly alleviated 6-OHDA-induced motor deficits in locomotor activity, akinesia, gait pattern and anxiety-like behavior, but not in apomorphine-induced rotations, recognition memory and depression-like behavior. Immunohistochemically, tyrosine hydroxylase (TH)-positive neurons in the substantia nigra were significantly preserved in the tDCS intervention group. ConclusionsThese results suggest that early and long-term tDCS could exert neuroprotective effects and reduce the aggravation of motor dysfunctions in a 6-OHDA-induced PD rat model. Furthermore, this preclinical model may enhance the promising possibility of the potential use of tDCS and serve as a translational platform to further identify the therapeutic mechanism of tDCS for PD or other neurological disorders.

Leptin mediates protection of hydrogen sulfide against 6-hydroxydopamine-induced Parkinson's disease: Involving enhancement in Warburg effect

BackgroundHydrogen sulfide (H2S) has therapeutic effects on Parkinson's disease (PD). Warburg effect, namely aerobic glycolysis, is benefit to PD. Leptin, a hormone secreted in adipose, plays an important role in the treatment of PD. ObjectiveTo determine whether the mechanism underlying protection of H2S against PD is involved in promoting Warburg effect via upregulation of leptin. MethodsWe set a PD model via unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA) in Sprague Dawley rat. PD-like behavior was analyzed by apomorphine-induced rotations, open field activity test, stepping test and cylinder test. Dopaminergic neurons were detected by immunohistochemistry. The expressions of Hexokinase-2, pyruvate kinase M-2, lactate dehydrogenase, pyruvate dehydrogenase kinase, pyruvate dehydrogenase, and leptin were measured by Western blot. Lactate dehydrogenase (LDHA) activity was monitored by ELISA. The lactate content was measured by lactate assay kit. ResultsWe showed that NaHS (a donor of H2S) prevented 6-OHDA-induced PD-like behaviors as well as the loss of dopaminergic neurons. We also found that NaHS enhanced the Warburg effect and upregulated leptin expression in the substantia nigra of 6-OHDA-exposed rats. While, inhibited leptin signaling by OBR13-A reversed the protections of H2S against 6-OHDA-exerted PD-like behaviors and the loss of dopaminergic neurons in the substantia nigra, and abolished H2S-enhanced in the Warburg effect in the substantia nigra. Conclusion: These data indicated that leptin mediates the protection of H2S against PD, which involves enhancing the Warburg effect of the substantia nigra.

L-linalool exerts a neuroprotective action on hemiparkinsonian rats.

Linalool (LIN) is a monoterpene, responsible for the aroma of essential oils in some species. It presents a sedative and anxiolytic potential, enhancing GABAergic currents and behaving as a benzodiazepine-type of drug. The objectives of the present work were to study the neuroprotective effects of LIN on a model of Parkinson's disease. For that, male Wistar rats were divided into the following groups: sham-operated (SO), 6-OHDA-lesioned, and 6-OHDA-lesioned and treated with LIN (25, 50, and 100mg/kg, p.o.) for 2weeks. Afterwards, the animals were subjected to behavioral tests (apomorphine-induced rotations, open field, and forced swimming tests). Then, the animals were euthanized, and the striatum, hippocampus, and prefrontal cortex were processed for neurochemistry (nitrite and lipoperoxidation measurements) and immunohistochemistry (TH and DAT) assays. The results were analyzed by ANOVA and Tukey's test for multiple comparisons and considered significant at p < 0.05. LIN significantly improved the behavioral alterations of the 6-OHDA-lesioned group, as evaluated by the apomorphine-induced rotations, open field, and forced swimming tests. In addition, LIN partially reversed the decreased DA, DOPAC, and HVA contents observed in the 6-OHDA-lesioned striatum. The untreated 6-OHDA group presented increased nitrite contents and lipoperoxidation in all the brain areas studied, and these changes were completely reversed after LIN treatments. Finally, LIN significantly prevented the reduction in TH and DAT expressions demonstrated in the right 6-OHDA-lesioned striatum. All these data strongly suggest that LIN presents a neuroprotective action in hemiparkinsonian rats, probably related to the drug anti-inflammatory and antioxidant activities.