Chronic high-sugar diet in adulthood protects Caenorhabditis elegans from 6-OHDA-induced dopaminergic neurodegeneration.

BACKGROUND: Diets high in saturated fat and sugar, termed "Western diets," have been associated with several negative health outcomes, including increased risk for neurodegenerative disease. Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and is characterized by the progressive death of dopaminergic neurons in the brain. We build upon previous work characterizing the impact of high-sugar diets in Caenorhabditis elegans to mechanistically evaluate the relationship between high-sugar diets and dopaminergic neurodegeneration. RESULTS: Adult high-glucose and high-fructose diets, or exposure from day 1 to 5 of adulthood, led to increased lipid content, shorter lifespan, and decreased reproduction. However, in contrast to previous reports, we found that adult chronic high-glucose and high-fructose diets did not induce dopaminergic neurodegeneration alone and were protective from 6-hydroxydopamine (6-OHDA) induced degeneration. Neither sugar altered baseline electron transport chain function and both increased vulnerability to organism-wide ATP depletion when the electron transport chain was inhibited, arguing against energetic rescue as a basis for neuroprotection. The induction of oxidative stress by 6-OHDA is hypothesized to contribute to its pathology, and high-sugar diets prevented this increase in the soma of the dopaminergic neurons. However, we did not find increased expression of antioxidant enzymes or glutathione levels. Instead, we found evidence suggesting downregulation of the dopamine reuptake transporter dat-1 that could result in decreased 6-OHDA uptake. CONCLUSIONS: Our work uncovers a neuroprotective role for high-sugar diets, despite concomitant decreases in lifespan and reproduction. Our results support the broader finding that ATP depletion alone is insufficient to induce dopaminergic neurodegeneration, whereas increased neuronal oxidative stress may drive degeneration. Finally, our work highlights the importance of evaluating lifestyle by toxicant interactions.

Shared GABA transmission pathology in dopamine agonist- and antagonist-induced dyskinesia.

Dyskinesia is involuntary movement caused by long-term medication with dopamine-related agents: the dopamine agonist 3,4-dihydroxy-L-phenylalanine (L-DOPA) to treat Parkinson's disease (L-DOPA-induced dyskinesia [LID]) or dopamine antagonists to treat schizophrenia (tardive dyskinesia [TD]). However, it remains unknown why distinct types of medications for distinct neuropsychiatric disorders induce similar involuntary movements. Here, we search for a shared structural footprint using magnetic resonance imaging-based macroscopic screening and super-resolution microscopy-based microscopic identification. We identify the enlarged axon terminals of striatal medium spiny neurons in LID and TD model mice. Striatal overexpression of the vesicular gamma-aminobutyric acid transporter (VGAT) is necessary and sufficient for modeling these structural changes; VGAT levels gate the functional and behavioral alterations in dyskinesia models. Our findings indicate that lowered type 2 dopamine receptor signaling with repetitive dopamine fluctuations is a common cause of VGAT overexpression and late-onset dyskinesia formation and that reducing dopamine fluctuation rescues dyskinesia pathology via VGAT downregulation.

Oral administration of Limonin (LM) exerts neuroprotective effects by inhibiting neuron autophagy and microglial activation in 6-OHDA-injected rats.

Parkinson's disease (PD) is a neurodegenerative disorder that occurs most frequently in middle-aged and elderly people. It is characterized by an insidious onset and a complex etiology, and no effective treatment has been developed. The primary characteristic of PD is the degenerative death of midbrain dopaminergic neurons. The excessive autophagy of neurons and hyperactivation of microglia were shown to be involved in the apoptosis of dopaminergic neurons. Limonin (LM), a type of pure natural compound present in grapefruit or citrus fruits (e. g., lemon, orange) has been reported to inhibit apoptosis and inflammation. However, its role and mechanism of action in PD are unclear. In this study, we explored the effect and mechanism of action of LM in PD. In vivo experiments revealed that LM ameliorated 6-OHDA-induced reduced motor activity and PD-related pathological damage in rats. In vitro experiments revealed that LM inhibited the 6-OHDA-induced apoptosis of PC12 cells by inhibiting the excessive autophagy of neurons. In addition, LM inhibited microglial inflammation by activating the AKT/Nrf-2/HO-1 pathway and protected neurons against microglial inflammation-mediated neurotoxicity. In conclusion, the findings of this experiment demonstrated that LM exerted neuroprotective effects by inhibiting neuronal autophagy-mediated apoptosis and microglial activation in 6-OHDA-injected rats, thus indicating that LM can serve as a candidate for PD by targeting neuroinflammation and neuronal autophagy to inhibit neuronal apoptosis.

Brainstem Modulates Parkinsonism-Induced Orofacial Sensorimotor Dysfunctions.

Parkinson's Disease (PD), treated with the dopamine precursor l-3,4-dihydroxyphenylalanine (L-DOPA), displays motor and non-motor orofacial manifestations. We investigated the pathophysiologic mechanisms of the lateral pterygoid muscles (LPMs) and the trigeminal system related to PD-induced orofacial manifestations. A PD rat model was produced by unilateral injection of 6-hydroxydopamine into the medial forebrain bundle. Abnormal involuntary movements (dyskinesia) and nociceptive responses were determined. We analyzed the immunodetection of Fos-B and microglia/astrocytes in trigeminal and facial nuclei and morphological markers in the LPMs. Hyperalgesia response was increased in hemiparkinsonian and dyskinetic rats. Hemiparkinsonism increased slow skeletal myosin fibers in the LPMs, while in the dyskinetic ones, these fibers decreased in the contralateral side of the lesion. Bilateral increased glycolytic metabolism and an inflammatory muscle profile were detected in dyskinetic rats. There was increased Fos-B expression in the spinal nucleus of lesioned rats and in the motor and facial nucleus in L-DOPA-induced dyskinetic rats in the contralateral side of the lesion. Glial cells were increased in the facial nucleus on the contralateral side of the lesion. Overall, spinal trigeminal nucleus activation may be associated with orofacial sensorial impairment in Parkinsonian rats, while a fatigue profile on LPMs is suggested in L-DOPA-induced dyskinesia when the motor and facial nucleus are activated.

Artemisinin Confers Neuroprotection against 6-OHDA-Induced Neuronal Injury In Vitro and In Vivo through Activation of the ERK1/2 Pathway.

Parkinson's disease (PD) is an age-related, progressive neurodegenerative disease characterized by the gradual and massive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). We have recently reported that artemisinin, an FDA-approved first-line antimalarial drug, possesses a neuroprotective effect. However, the effects and underlying mechanisms of artemisinin on Parkinson's disease remain to be elucidated. In this study, we investigated the neuroprotective effects of artemisinin on 6-OHDA and MPP+ in neuronal cells and animal models, as well as the underlying mechanisms. Our results showed that artemisinin significantly attenuated the loss of cell viability, LDH release, elevated levels of reactive oxygen species (ROS), the collapse of the mitochondria trans-membrane potential and cell apoptosis in PC12 cells. Western blot results showed that artemisinin stimulated the phosphorylation of ERK1/2, its upstream signaling proteins c-Raf and MEK and its downstream target CREB in PC12 cells in a time- and concentration-dependent manner. In addition, the protective effect of artemisinin was significantly reduced when the ERK pathway was blocked using the ERK pathway inhibitor PD98059 or when the expression of ERK was knocked down using sgRNA. These results indicate the essential role of ERK in the protective effect of artemisinin. Similar results were obtained in SH-SY5Y cells and primary cultured neurons treated with 6-OHDA, as well as in cellular models of MPP+ injury. More interestingly, artemisinin attenuated PD-like behavior deficit in mice injected with 6-OHDA evaluated by behavioral tests including swimming test, pole-test, open field exploration and rotarod tests. Moreover, artemisinin also stimulated the phosphorylation of ERK1/2, inhibited apoptosis, and rescued dopaminergic neurons in SNc of these animals. Application of ERK pathway inhibitor PD98059 blocked the protective effect of artemisinin in mice during testing. Taking these results together, it was indicated that artemisinin preserves neuroprotective effects against 6-OHDA and MPP+ induced injury both in vitro and in vivo by the stimulation of the ERK1/2 signaling pathway. Our findings support the potential therapeutic effect of artemisinin in the prevention and treatment of Parkinson's disease.

Lactiplantibacillus plantarum PS128 Alleviates Exaggerated Cortical Beta Oscillations and Motor Deficits in the 6-Hydroxydopamine Rat Model of Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by midbrain dopaminergic neuronal loss and subsequent physical impairments. Levodopa manages symptoms best, while deep brain stimulation (DBS) is effective for advanced PD patients; however, side effects occur with the diminishing therapeutic window. Recently, Lactiplantibacillus plantarum PS128 (PS128) was found to elevate dopamine levels in rodent brains, suggesting its potential to prevent PD. Here, the therapeutic efficacy of PS128 was examined in the 6-hydroxydopamine rat PD model. Suppression of the power spectral density of beta oscillations (beta PSD) in the primary motor cortex (M1) was recorded as the indicator of disease progression. We found that 6 weeks of daily PS128 supplementation suppressed M1 beta PSD as well as did levodopa and DBS. Long-term normalization of M1 beta PSD was found in PS128-fed rats, whereas levodopa and DBS showed only temporal effects. PS128 + levodopa and PS128 + DBS exhibited better therapeutic effects than did levodopa + DBS or either alone. Significantly improved motor functions in PS128-fed rats were correlated with normalization of M1 beta PSD. Brain tissue analyses further demonstrated the role of PS128 in dopaminergic neuroprotection and the enhanced availability of neurotransmitters. These findings suggest that psychobiotic PS128 might be used alongside conventional therapies to treat PD patients.

Severity Assessment of Complex and Repeated Intracranial Surgery in Rats.

INTRODUCTION: Evidence-based grading of the impact of intracranial surgery on rat's well-being is important for ethical and legal reasons. We assessed the severity of complex and repeated intracranial surgery in a 6-hydroxydopamine (6-OHDA) Parkinson's rat model with subsequent intracranial electrode implantation and in an intracranial tumor model with subsequent resection. METHODS: Stereotactic surgery was performed in adult male rats with the same general anesthesia and perioperative pain management. In Parkinson's model, Sprague Dawley rats received unilateral injection of 6-OHDA (n = 11) or vehicle (n = 7) into the medial forebrain bundle as first operation (1st OP). After four weeks, neural electrodes were implanted in all rats as second operation (2nd OP). For tumor formation, BDIX/UlmHanZtm rats (n = 8) received frontocortical injection of BT4Ca cells as 1st OP, followed by tumor resection as 2nd OP after one week. Multiple measures severity assessment was done two days before and four days after surgery in all rats, comprising clinical scoring, body weight, and detailed behavioral screening. To include a condition with a known burden, rats with intracranial tumors were additionally assessed up to a predefined humane endpoint that has previously been classified as "moderate". RESULTS: After the 1st OP, only 6-OHDA injection resulted in transient elevated clinical scores, a mild long-lasting weight reduction, and motor disturbances. After the second surgery, body weight was transiently reduced in all groups. All other parameters showed variable results. Principal component analysis showed a separation from the preoperative state driven by motor-related parameters after 6-OHDA injection, while separation after electrode implantation and more clearly after tumor resection was driven by pain-related parameters, although not reaching the level of the humane endpoint of our tumor model. CONCLUSION: Overall, cranial surgery of different complexity only transiently and rather mildly affects rat's well-being. Multiple measures assessment allows the differentiation of model-related motor disturbances in Parkinson's model from potentially pain-related conditions after tumor resection and electrode implantation.

Effect of Natural Adenylcyclase/cAMP/CREB Signalling Activator Forskolin against Intra-Striatal 6-OHDA-Lesioned Parkinson's Rats: Preventing Mitochondrial, Motor and Histopathological Defects.

Parkinson's disease (PD) is characterised by dopaminergic neuronal loss in the brain area. PD is a complex disease that deteriorates patients' motor and non-motor functions. In experimental animals, the neurotoxin 6-OHDA induces neuropathological, behavioural, neurochemical and mitochondrial abnormalities and the formation of free radicals, which is related to Parkinson-like symptoms after inter-striatal 6-OHDA injection. Pathological manifestations of PD disrupt the cAMP/ATP-mediated activity of the transcription factor CREB, resulting in Parkinson's-like symptoms. Forskolin (FSK) is a direct AC/cAMP/CREB activator isolated from Coleus forskohlii with various neuroprotective properties. FSK has already been proven in our laboratory to directly activate the enzyme adenylcyclase (AC) and reverse the neurodegeneration associated with the progression of Autism, Multiple Sclerosis, ALS, and Huntington's disease. Several behavioural paradigms were used to confirm the post-lesion effects, including the rotarod, open field, grip strength, narrow beam walk (NBW) and Morris water maze (MWM) tasks. Our results were supported by examining brain cellular, molecular, mitochondrial and histopathological alterations. The FSK treatment (15, 30 and 45 mg/kg, orally) was found to be effective in restoring behavioural and neurochemical defects in a 6-OHDA-induced experimental rat model of PD. As a result, the current study successfully contributes to the investigation of FSK's neuroprotective role in PD prevention via the activation of the AC/cAMP/PKA-driven CREB pathway and the restoration of mitochondrial ETC-complex enzymes.

[Inhibition connexin 43 by mimetic peptide Gap27 mediates protective effects on 6-hydroxydopamine induced Parkinson's disease mouse model].

OBJECTIVE: To explore whether the using of mimetic peptide Gap27, a selective inhibitor of connexin 43 (Cx43), could block the death of dopamine neurons and influence the expression of Cx43 in 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease mouse models. METHODS: Eighteen C57BL/6 mice were randomly divided into control group, 6-OHDA group and 6-OHDA+Gap27 group, with 6 mice in each group. Bilateral substantia nigra stereotactic injection was performed. The control group was injected with ascorbate solution, 6-OHDA group was injected with 6-OHDA solution, and 6-OHDA+Gap27 group was injected with 6-OHDA and Gap27 mixed solution. Immuno-histochemical staining was used to detect the number of dopamine neurons, quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of Cx43 messenger ribonucleic acid (mRNA), immuno-fluorescence staining was used to detect the distribution of Cx43 protein, the contents of Cx43 protein and Cx43 phosphorylation at serine 368 (Cx43-ps368) in mouse midbrain were detected by Western blot. RESULTS: After injection of 6-OHDA, numerous dopamine neurons in substantia nigra died as Cx43 content increased, Cx43-ps368 content decreased. Mixing Gap27 while injecting 6-OHDA could reduce the number of death dopamine neurons and weaken the changes of Cx43 and Cx43-ps368 content caused by 6-OHDA. The number of tyrosine hydroxylase (TH) immunoreactive positive neurons in 6-OHDA group decreased to 27.7% ± 0.02% of the control group (P < 0.01); The number of TH immunoreactive positive neurons in 6-OHDA+Gap27 group was (1.64±0.16) times higher than that in 6-OHDA group (P < 0.05); The content of total Cx43 protein in 6-OHDA group was (1.44±0.07) times higher than that in 6-OHDA+Gap27 group (P < 0.05) while (1.68±0.07) times higher than that in control group (P < 0.01). In 6-OHDA group, the content of Cx43-ps368 protein and its proportion in total Cx43 protein were significantly lower than that in 6-OHDA+Gap27 group (P < 0.05). CONCLUSION: In 6-OHDA mouse models, mimetic peptide Gap27 played a protective role in reducing the damage to substantia nigra dopamine neurons, which was induced by 6-OHDA. The overexpression of Cx43 protein might have neurotoxicity to dopamine neuron. Meanwhile, decreasing Cx43 protein level and keeping Cx43-ps368 protein level may be the protective mechanisms of Gap27.

Dopamine depletion in wistar rats with epilepsy.

The dopamine content in cerebral structures has been related to neuronal excitability and several approaches have been used to study this phenomenon during seizure vulnerability period. In the present work, we describe the effects of dopamine depletion after the administration of 6-hidroxidopamine (6-OHDA) into the substantia nigra pars compacta of male rats submitted to the pilocarpine model of epilepsy. Susceptibility to pilocarpine-induced status epilepticus (SE), as well as spontaneous and recurrent seizures (SRSs) frequency during the chronic period of the model were determined. Since the hippocampus is one of main structures in the development of this experimental model of epilepsy, the dopamine levels in this region were also determined after drug administration. In the first experiment, 62% (15/24) of 6-OHDA pre-treated rats and 45% (11/24) of those receiving ascorbic acid as control solution progressed to motor limbic seizures evolving to SE, after the administration of pilocarpine. Severeness of seizures during the model´s the acute period, was significantly higher in epileptic experimental rats (56.52%), than in controls (4.16%). In the second experiment, the frequency of seizures in the model's chronic phase did not significantly change between groups. Our data show that dopamine may play an important role on seizure severity in the pilo's model acute period, which seems to be due to dopamine inhibitory action on motor expression of seizure.

Vitamin K2 Modulates Mitochondrial Dysfunction Induced by 6-Hydroxydopamine in SH-SY5Y Cells via Mitochondrial Quality-Control Loop.

Vitamin K2, a natural fat-soluble vitamin, is a potent neuroprotective molecule, owing to its antioxidant effect, but its mechanism has not been fully elucidated. Therefore, we stimulated SH-SY5Y cells with 6-hydroxydopamine (6-OHDA) in a proper dose-dependent manner, followed by a treatment of vitamin K2. In the presence of 6-OHDA, cell viability was reduced, the mitochondrial membrane potential was decreased, and the accumulation of reactive oxygen species (ROS) was increased. Moreover, the treatment of 6-OHDA promoted mitochondria-mediated apoptosis and abnormal mitochondrial fission and fusion. However, vitamin K2 significantly suppressed 6-OHDA-induced changes. Vitamin K2 played a significant part in apoptosis by upregulating and downregulating Bcl-2 and Bax protein expressions, respectively, which inhibited mitochondrial depolarization, and ROS accumulation to maintain mitochondrial structure and functional stabilities. Additionally, vitamin K2 significantly inhibited the 6-OHDA-induced downregulation of the MFN1/2 level and upregulation of the DRP1 level, respectively, and this enabled cells to maintain the dynamic balance of mitochondrial fusion and fission. Furthermore, vitamin K2 treatments downregulated the expression level of p62 and upregulated the expression level of LC3A in 6-OHDA-treated cells via the PINK1/Parkin signaling pathway, thereby promoting mitophagy. Moreover, it induced mitochondrial biogenesis in 6-OHDA damaged cells by promoting the expression of PGC-1α, NRF1, and TFAM. These indicated that vitamin K2 can release mitochondrial damage, and that this effect is related to the participation of vitamin K2 in the regulation of the mitochondrial quality-control loop, through the maintenance of the mitochondrial quality-control system, and repair mitochondrial dysfunction, thereby alleviating neuronal cell death mediated by mitochondrial damage.

Burrowing behaviour of rats: Strain differences and applicability as well-being parameter after intracranial surgery.

In mice, burrowing is considered a species-typical parameter for assessing well-being, while this is less clear in rats. This exploratory study evaluated burrowing behaviour in three rat strains during training and in the direct postoperative phase after complex intracranial surgery in different neuroscience rat models established at Hannover Medical School or Aachen University Hospital. Male Crl:CD (SD; n = 18), BDIX/UlmHanZtm (BDIX; n = 8) and RjHan:WI (Wistar; n = 35) rats were individually trained to burrow gravel out of a tube on four consecutive days. Thereafter, BDIX rats were subjected to intracranial injection of BT4Ca cells and tumour resection (rat glioma model), SD rats to injection of 6-hydroxydopamine (6-OHDA) or vehicle (rat Parkinson's disease model) and Wistar rats to endovascular perforation or sham surgery (rat subarachnoid haemorrhage (SAH) model). Burrowing was retested on the day after surgery. During training, BDIX rats burrowed large amounts (mean of 2370 g on the fourth day), while SD and Wistar rats burrowed less gravel (means of 846 and 520 g, respectively). Burrowing increased significantly during training only in Wistar rats. Complex surgery, that is, tumour resection (BDIX), 6-OHDA injection (SD) and endovascular perforation or sham surgery for SAH (Wistar) significantly reduced burrowing and body weight, while simple stereotactic injection of tumour cells or vehicle did not affect burrowing. Despite the training, burrowing differed between the strains. In the direct postoperative phase, burrowing was reduced after complex surgery, indicating reduced well-being. Reduced burrowing was accompanied with postoperative weight loss, a validated and recognised quantitative measure for severity assessment.

Central high mobility group box-1 induces mechanical hypersensitivity with spinal microglial activation in a mouse model of hemi-Parkinson's disease.

Parkinson's disease (PD) patients often complain of pain, but this problem has been neglected and is poorly understood. High mobility group box-1 (HMGB1), an alarmin/damage-associated molecular patterns protein, is increased in the cerebrospinal fluid in PD patients. However, little is known of the relationship between HMGB1 and pain associated with PD. Here, we investigated the role of central HMGB1 in the regulation of nociceptive hypersensitivity in a mouse model of PD. Male ddY mice were microinjected unilaterally with 6-hydroxydopamine (6OHDA) into the striatum. These hemi-PD mice were treated with anti-HMGB1 neutralizing antibody (nAb; 10 µg in 10 µL) by intranasal (i.n.) administration. The mechanical hypersensitivity of the hind paws was evaluated with the von Frey test. Spinal microglial activity was analyzed by immunostaining for ionized calcium-binding adapter molecule 1. The 6OHDA-administered mice displayed unilateral loss of dopamine neurons in the substantia nigra and mechanical hypersensitivity in both hind paws. Moreover, spinal microglia were activated in these hemi-PD mice. Twenty-eight days after the 6OHDA injections, repeated i.n., but not systemic, treatment with anti-HMGB1 nAb inhibited the bilateral mechanical hypersensitivity and spinal microglial activation. However, the anti-HMGB1 nAb did not ameliorate the dopamine neuron loss. Moreover, intracerebroventricular injection with recombinant HMGB1 induced mechanical hypersensitivity. These findings indicate that HMGB1 is involved in the maintenance of nociceptive symptoms in hemi-PD mice via spinal microglial activation. Therefore, central HMGB1 may have potential as a therapeutic target for pain associated with PD.

Induction and Assessment of Levodopa-induced Dyskinesias in a Rat Model of Parkinson's Disease.

Levodopa (L-DOPA) remains the gold-standard therapy used to treat Parkinson's disease (PD) motor symptoms. However, unwanted involuntary movements known as L-DOPA-induced dyskinesias (LIDs) develop with prolonged use of this dopamine precursor. It is estimated that the incidence of LIDs escalates to approximately 90% of individuals with PD within 10-15 years of treatment. Understanding the mechanisms of this malady and developing both novel and effective anti-dyskinesia treatments requires consistent and accurate modeling for pre-clinical testing of therapeutic interventions. A detailed method for reliable induction and comprehensive rating of LIDs following 6-OHDA-induced nigral lesioning in a rat model of PD is presented here. Dependable LID assessment in rats provides a powerful tool that can be readily utilized across laboratories to test emerging therapies focused on reducing or eliminating this common treatment-induced burden for individuals with PD.

Quantitative analysis of neuronal mitochondrial movement reveals patterns resulting from neurotoxicity of rotenone and 6-hydroxydopamine.

Alterations in mitochondrial dynamics, including their intracellular trafficking, are common early manifestations of neuronal degeneration. However, current methodologies used to study mitochondrial trafficking events rely on parameters that are primarily altered in later stages of neurodegeneration. Our objective was to establish a reliable applied statistical analysis to detect early alterations in neuronal mitochondrial trafficking. We propose a novel quantitative analysis of mitochondria trajectories based on innovative movement descriptors, including straightness, efficiency, anisotropy, and kurtosis. We evaluated time- and dose-dependent alterations in trajectory descriptors using biological data from differentiated SH-SY5Y cells treated with the mitochondrial toxicants 6-hydroxydopamine and rotenone. MitoTracker Red CMXRos-labelled mitochondria movement was analyzed by total internal reflection fluorescence microscopy followed by computational modelling to describe the process. Based on the aforementioned trajectory descriptors, this innovative analysis of mitochondria trajectories provides insights into mitochondrial movement characteristics and can be a consistent and sensitive method to detect alterations in mitochondrial trafficking occurring in the earliest time points of neurodegeneration.

Role of 5-HT1A Receptor in Vilazodone-Mediated Suppression of L-DOPA-Induced Dyskinesia and Increased Responsiveness to Cortical Input in Striatal Medium Spiny Neurons in an Animal Model of Parkinson's Disease.

L-DOPA therapy in Parkinson's disease (PD) is limited due to emerging L-DOPA-induced dyskinesia. Research has identified abnormal dopamine release from serotonergic (5-HT) terminals contributing to this dyskinesia. Selective serotonin reuptake inhibitors (SSRIs) or 5-HT receptor (5-HTr) agonists can regulate 5-HT activity and attenuate dyskinesia, but they often also produce a loss of the antiparkinsonian efficacy of L-DOPA. We investigated vilazodone, a novel multimodal 5-HT agent with SSRI and 5-HTr1A partial agonist properties, for its potential to reduce dyskinesia without interfering with the prokinetic effects of L-DOPA, and underlying mechanisms. We assessed vilazodone effects on L-DOPA-induced dyskinesia (abnormal involuntary movements, AIMs) and aberrant responsiveness to corticostriatal drive in striatal medium spiny neurons (MSNs) measured with in vivo single-unit extracellular recordings, in the 6-OHDA rat model of PD. Vilazodone (10 mg/kg) suppressed all subtypes (axial, limb, orolingual) of AIMs induced by L-DOPA (5 mg/kg) and the increase in MSN responsiveness to cortical stimulation (shorter spike onset latency). Both the antidyskinetic effects and reversal in MSN excitability by vilazodone were inhibited by the 5-HTr1A antagonist WAY-100635, demonstrating a critical role for 5-HTr1A in these vilazodone actions. Our results indicate that vilazodone may serve as an adjunct therapeutic for reducing dyskinesia in patients with PD.

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

BACKGROUND: 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. METHODS AND RESULTS: To establish Parkinson's Disease (PD) model in cell culture conditions, SH-SY5Y cells were exposed to 200 µM 6-OHDA for 1 day. Prior to 6-OHDA treatment, SH-SY5Y cells had been pre-treated with bromelain (25 µg/mL, 50 µg/mL, 75 µg/mL and 100 µg/mL). After 1 day, 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. CONCLUSIONS: These findings indicated that bromelain, with its neuroprotective features can be useful for neuroprotection in PD.

Magnetothermal nanoparticle technology alleviates parkinsonian-like symptoms in mice.

Deep brain stimulation (DBS) has long been used to alleviate symptoms in patients suffering from psychiatric and neurological disorders through stereotactically implanted electrodes that deliver current to subcortical structures via wired pacemakers. The application of DBS to modulate neural circuits is, however, hampered by its mechanical invasiveness and the use of chronically implanted leads, which poses a risk for hardware failure, hemorrhage, and infection. Here, we demonstrate that a wireless magnetothermal approach to DBS (mDBS) can provide similar therapeutic benefits in two mouse models of Parkinson's disease, the bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and in the unilateral 6-hydroxydopamine (6-OHDA) model. We show magnetothermal neuromodulation in untethered moving mice through the activation of the heat-sensitive capsaicin receptor (transient receptor potential cation channel subfamily V member 1, TRPV1) by synthetic magnetic nanoparticles. When exposed to an alternating magnetic field, the nanoparticles dissipate heat, which triggers reversible firing of TRPV1-expressing neurons. We found that mDBS in the subthalamic nucleus (STN) enables remote modulation of motor behavior in healthy mice. Moreover, mDBS of the STN reversed the motor deficits in a mild and severe parkinsonian model. Consequently, this approach is able to activate deep-brain circuits without the need for permanently implanted hardware and connectors.

Neuroprotective effect of bone marrow-derived mesenchymal stem cell secretome in 6-OHDA-induced Parkinson's disease.

Aim: The aim of the study was to evaluate the neuroprotective effect of bone marrow stem cell secretome in the 6-hydroxydopamine (6-OHDA) model of Parkinson's disease. Materials & methods: Secretome prepared from mesenchymal stem cells of 3-month-old rats was injected daily for 7 days between days 7 and 14 after 6-OHDA administration. After 14 days, various neurobehavioral parameters were conducted. These behavioral parameters were further correlated with biochemical and molecular findings. Results & conclusion: Impaired neurobehavioral parameters and increased inflammatory, oxidative stress and apoptotic markers in the 6-OHDA group were significantly modulated by secretome-treated rats. In conclusion, mesenchymal stem cell-derived secretome could be further explored for the management of Parkinson's disease.

Resveratrol Alleviates Levodopa-Induced Dyskinesia in Rats.

Dyskinesia is a serious complication of Parkinson's disease during levodopa (L-DOPA) treatment. The pathophysiology of L-DOPA-induced dyskinesia (LID) is complex and not fully illuminated. At present, treatment of dyskinesia is quite limited. Recent studies demonstrated neuroinflammation plays an important role in development of LID. Thus, inhibition of neuroinflammation might open a new avenue for LID treatment. Resveratrol (RES) is the most well-known polyphenolic stilbenoid and verified to possess a large variety of biological activities. DA neurotoxicity was assessed via behavior test and DA neuronal quantification. The movement disorders of dyskinesia were detected by the abnormal involuntary movements scores analysis. Effects of RES on glial cells-elicited neuroinflammation were also explored. Data showed that RES attenuated dyskinesia induced by L-DOPA without affecting L-DOPA's anti-parkinsonian effects. Furthermore, RES generated neuroprotection against long term treatment of L-DOPA-induced DA neuronal damage. Meanwhile, RES reduced protein expression of dyskinesia molecular markers, ΔFOS B and ERK, in the striatum. Also, there was a strong negative correlation between DA system damage and ΔFOS B level in the striatum. In addition, RES inhibited microglia and astroglia activation in substantia nigra and subsequent inflammatory responses in the striatum during L-DOPA treatment. RES alleviates dyskinesia induced by L-DOPA and these beneficial effects are closely associated with protection against DA neuronal damage and inhibition of glial cells-mediated neuroinflammatory reactions.