Anti-Inflammatory and Neuroprotective Effects of a Novel Water-Soluble Formulation of Coenzyme-Q10 and Ashwagandha Root Extract in a Paraquat-Induced Rat Model of Parkinson’s Disease

Neuroprotective effect of resveratrol on 6-OHDA-induced Parkinson's disease in rats

Adeno-associated Virus-mediated, Mifepristone-regulated Transgene Expression in the Brain

ObjectiveThis research was aimed to investigate the effects of baicalin on 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson’s disease (PD) and the main mechanism of baicalin based on metabolomics.MethodsThe rat model of PD was induced by 6-OHDA. The protective effects of baicalin on rat model of PD were evaluated by open field test and rotarod test. The anti-PD efficacy of baicalin was evaluated by examining the morphologic changes of neurons and the level of monoamine neurotransmitters in the striatum, the number and morphology of tyrosine hydroxylase (TH)-positive neurons, and oxidative stress. Combined with metabolomics methods, the pharmacodynamic mechanism of baicalin on PD pathogenesis was also explored.ResultsBaicalin treatment improved the rod time and voluntary movement in rat model of PD (P<0.05) by the open field test and rotarod test. In addition, baicalin also protected from oxidative stress injury (P<0.05), and regulated the content of monoamine neurotransmitters dopamine, 3,4-dihydroxyphenylacetic acid, 5-hydroxytryptamine, and 5-hydroxyindoleacetic acid (P<0.05) and the number and morphology of TH-positive cells in 6-OHDA-induced PD model rats. By metabolomics, multivariate statistical analysis, and receiver operating characteristic curve analysis, we found that two metabolites N-acetyl aspartic acid and glutamic acid had a good diagnostic value. Quantitative analysis of metabolites showed a regulatory function of baicalin.ConclusionBaicalin has significant protective effect on 6-OHDA-induced PD rats, which may play a protective role through an antioxidant, promoting the release of neurotransmitters and regulating the metabolism of N-acetyl aspartate and glutamate.

In clinical practice, deep brain stimulation (DBS) is effective for treatment of motor symptoms in Parkinson’s disease (PD). However, the mechanisms have not been understood completely. There are some reports that electrical stimulation exerts neuroprotective effects on the central nervous system diseases including cerebral ischemia, head trauma, epilepsy and PD, although there are a few reports on neuroprotective effects of spinal cord stimulation (SCS). We investigated the neuroprotective effects of high cervical SCS on PD model of rats. Adult female Sprague-Dawley rats received hour-long SCS (2, 50 or 200 Hz) with an epidural electrode at C1–2 level for 16 consecutive days. At 2 days after initial SCS, 6-hydroxydopamine (6-OHDA) was injected into the right striatum of rats. Behavioral evaluations of PD symptoms were employed, including cylinder test and amphetamine-induced rotation test performed at 1 and 2 weeks after 6-OHDA injection. Animals were subsequently euthanized for immunohistochemical investigations. In order to explore neurotrophic and growth factor upregulation induced by SCS, another cohort of rats that received 50 Hz SCS was euthanized at 1 and 2 weeks after lesion for protein assays. Behavioral tests revealed that the number of amphetamine-induced rotations decreased in SCS groups. Immunohistochemically, tyrosine hydroxylase (TH)-positive fibers in the striatum were significantly preserved in SCS groups. TH-positive neurons in the substantia nigra pars compacta were significantly preserved in 50 Hz SCS group. The level of vascular endothelial growth factor (VEGF) was upregulated by SCS at 1 week after the lesion. These results suggest that high cervical SCS exerts neuroprotection in PD model of rats, at least partially by upregulation of VEGF. SCS is supposed to suppress or delay PD progression and might become a less invasive option for PD patients, although further preclinical and clinical investigations are needed to confirm the effectiveness and safety.

The present study investigates the neuroprotective effects of the sea urchin Paracentrotus lividus gonadal extract on rotenone-induced neurotoxicity in a Parkinson's disease (PD) rat model. Parkinson's disease, characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN), is exacerbated by oxidative stress and neuroinflammation. The study involved fifty Wistar rats divided into five groups: control, dimethyl sulfoxide (DMSO) control, Paracentrotus lividus gonadal extract-treated, rotenone-treated, and combined rotenone with Paracentrotus lividus gonadal extract-treated. Behavioral assessments included the rotarod and open field tests, while biochemical analyses measured oxidative stress markers (malondialdehyde (MDA), nitric oxide (NO), glutathione (GSH)), antioxidants (superoxide dismutase (SOD), catalase (CAT)), pro-inflammatory cytokines (interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α)), and neurotransmitters (dopamine (DA), levodopa (L-Dopa)). Histological and immunohistochemical analyses evaluated the neuronal integrity and tyrosine hydroxylase (TH) and alpha-synuclein expression. The results showed that Paracentrotus lividus gonadal extract significantly mitigated rotenone-induced motor deficits and improved locomotor activity. Biochemically, the extract reduced oxidative stress and inflammation markers while enhancing antioxidant levels. Histologically, it restored neuronal integrity and reduced alpha-synuclein accumulation. Molecularly, it increased tyrosine hydroxylase and dopa decarboxylase gene expression, essential for dopamine synthesis. These findings suggest that Paracentrotus lividus gonadal extract exerts neuroprotective effects by modulating oxidative stress, neuroinflammation, and dopaminergic neuron integrity, highlighting its potential as a therapeutic agent for Parkinson's disease.

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

Troxerutin exerts neuroprotection in 6-hydroxydopamine lesion rat model of Parkinson’s disease: Possible involvement of PI3K/ERβ signaling

Objective To explore the effects of constraint-induced movement therapy (CIMT) on the expression of tyrosine hydroxylase (TH) and glial cell derived neurotrophic factor (GDNF) in Parkinson's disease (PD) model rats. Methods PD models were established by microinjection of 6-hydroxydopamine (6-OHDA) solution into substantia nigra of rats' right cerebral hemisphere.Forty-two model rats were divided randomly into an exercise group and a control group 1 week after microinjection.The exercise group rats were forced to use their impaired limbs by placing their nonimpaired fore-limbs in casts.The control group rats were housed in the same environment without any special treatment.Two weeks after 6-OHDA infusion and exercise training,the behavioral changes of rats were examined after intraperitoneal injection apomorphine ( APO).The content of dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) was measured by high performance liquid chromatography with electrochemistry ( HPLAEC) ; the expressions of TH and GDNF in striatum were detected by immunohistochemical methods and TH,GDNF mRNA were detected by reverse transcription-polymerase chain reaction (RT-PCR). Results After 2 weeks of training,the rotating laps of the rats in exercise group within 30 min after APO induction,reduced to a significantly greater extent when compared to the control group (P ＜ 0.05).The content of DA and it's metabolites DOPAC in striatum homogenate was significantly higher in exercise group than that in the control group ( P ＜ 0.05 ),and the expression levels,of TH and GDNF protein/ mRNA were also significantly higher in the exercise group than those in control group ( P ＜ 0.05 ). Conclusions CIMT can improve the behavioral performance of PD rats,probably through promoting the expressions of TH and GDNF protein/mRNA in striatum,and increasing DA and it's metabolites DOPAC level. Key words: Constraint-induced movement therapy; Parkinson's disease; Dopamine; Tyrosine hydroxylase; Glial cell derived neurotrophic factor

6-Hydroxydopamine induces distinct alterations in GDF5 and GDNF mRNA expression in the rat nigrostriatal system in vivo

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer’s disease. The principal pathological feature of PD is the progressive loss of dopaminergic neurons in the ventral midbrain. This pathology involves several cellular alterations: oxidative stress, mitochondrial dysfunction, loss of proteostasis, and autophagy impairment. Moreover, in recent years, lipid metabolism alterations have become relevant in PD pathogeny. The modification of lipid metabolism has become a possible way to treat the disease. Because of this, we analyzed the effect and possible mechanism of action of linoleic acid (LA) on an SH-SY5Y PD cell line model and a PD mouse model, both induced by 6-hydroxydopamine (6-OHDA) treatment. The results show that LA acts as a potent neuroprotective and anti-inflammatory agent in these PD models. We also observed that LA stimulates the biogenesis of lipid droplets and improves the autophagy/lipophagy flux, which resulted in an antioxidant effect in the in vitro PD model. In summary, we confirmed the neuroprotective effect of LA in vitro and in vivo against PD. We also obtained some clues about the novel neuroprotective mechanism of LA against PD through the regulation of lipid droplet dynamics.

The purpose of this study is to clarify that exercise may improve the motor dysfunction of Parkinson's disease (PD) model rats by increasing the reuptake of glutamate (Glu) in the striatum. The neurotoxin 6-hydroxydopamine (6-OHDA) was injected into the medial forebrain bundle (MFB) of the rats' right brain to establish PD model rats with unilateral injury, and the sham operation group was given the same dose of normal saline at the same site as the control group. The reliability of the model was evaluated by apomorphine (APO)-induced rotation test combined with tyrosine hydroxylase (TH) immunohistochemical staining in the substantia nigra and striatum. The exercise group started treadmill training intervention (11m/min, 30min/day, 5d/week, and 4weeks in total) 1 week after the operation. The balance bar test, suspension test, and the tail-lifting handstand test were used to evaluate exercise performance of rats; RT-PCR and western blotting were used to detect protein and mRNA expression of glutamate transporter-1 (GLT-1) and glutamine synthetase (GS) in the striatum; and isotope labeling was used to detect the ability of Glu reuptake in the striatum. (1) Compared with PD group, the number of TH immunoreactive cells in the substantia nigra and the content of TH immunoreactive fibers in the striatum did not change significantly in PD + Ex group. (2) Compared with PD group, the latency and total time of crossing the balance beam were significantly shorter (P < 0.01), the retention time of two forepaws on the metal wire was significantly longer (P < 0.01), the maximum lifting of head and trunk was significantly increased (P < 0.01) in PD + Ex group. (3) Compared with PD group, the ability of Glu reuptake in the striatum was significantly increased (P < 0.05), the expression levels of GLT-1 and GS mRNA in the striatum were significantly increased (P < 0.05), the protein expression of GLT-1 and GS in the striatum was significantly upregulated (P < 0.05) in PD + Ex group. Exercise intervention can significantly improve the motor dysfunction of PD model rats, increase the ability of striatal Glu reuptake significantly, and upregulate the expression levels of GLT-1 and GS protein and GS mRNA significantly. Exercise intervention may increase the protein expression level of GLT-1 and increase the reuptake ability of Glu in the striatum, thereby reducing the excitotoxic effect of excessive Glu on the postsynaptic membrane, and ultimately alleviate the motor dysfunction in PD model rats.

Autotransplantation for Parkinson's disease goes a step further.

Objective: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has evolved as a powerful therapeutic alternative for the treatment of Parkinson’s disease (PD). Despite its clinical efficacy, the mechanisms of action have remained poorly understood. In addition to the immediate symptomatic effects, long-term neuroprotective effects have been suggested. Those may be mediated through neurotrophic factors (NFs) like vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF). Here, the impact of DBS on the expression of NFs was analysed in a rat model of PD. Methods: Unilateral 6-hydroxydopamine (6-OHDA) lesioned rats received DBS in the STN using an implantable microstimulation system, sham DBS in the STN, or no electrode placement. Continuous unilateral STN-DBS (current intensity 50 µA, frequency 130 Hz, and pulse width 52 µs) was conducted for 14 days. Rats were then sacrificed and brains shock frozen. Striata and motor cortices were dissected with a cryostat. Levels of VEGF, BDNF, and GDNF were analysed, both by quantitative PCR and colorimetric ELISA. Results: PCR revealed a significant upregulation of only BDNF mRNA in the ipsilateral striata of the DBS group, when compared to the sham-stimulated group. There was no significant increase in VEGF mRNA or GDNF mRNA. ELISA analysis showed augmentations of BDNF, VEGF, as well as GDNF protein in the ipsilateral striata after DBS compared to sham stimulation. In the motor cortex, significant increases after DBS were observed for BDNF only, not for the other 2 NFs. Conclusions: The upregulation of trophic factors induced by STN-DBS may participate in its long-term therapeutic efficacy and potentially neuroprotective effects.

Quantification of brainstem norepinephrine relative to vocal impairment and anxiety in the Pink1-/- rat model of Parkinson disease

Parkinson disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. The resulting failure of the nigrostriatal pathway leads to profound dopamine deficiency, causing bradykinesia, tremor, rigidity and postural imbalance. The current therapeutic options for this disabling disorder remain symptomatic and are devoid of any impact on the neurodegeneration process per se. The development of neuroprotective and regenerative strategies constitute therefore an important challenge, in order to halt and possibly reverse the loss of the nigrostriatal pathway in PD. In the present study, we have investigated two different approaches to protect or restore the nigrostriatal dopaminergic system in rodent models of PD. In the first part, we examined the potential of a spontaneous dominant mutation in mice called slow Wallerian degeneration (Wlds) to confer protection of the dopaminergic pathway against the catecholaminergic toxin 6-hydroxydopamine (6-OHDA). Interestingly, the Wlds fusion protein proved capable to provide functional preservation of the nigrostriatal dopaminergic terminals. The observed Wlds-mediated protection of dopaminergic axons might help to further elucidate the mechanisms leading to the loss of dopamine axons in PD and conduct to the development of new therapeutic modalities for this disorder. In the second approach, we assessed the protective and regenerative potential of the neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) delivered via capsules in a rat model of PD. GDNF delivery by encapsulated cells resulted in regeneration of dopaminergic fibers and behavioral improvement in a bilateral 6-OHDA model in the rat. Importantly, GDNF withdrawal did not affect the morphological and behavioral effects in our model. The sustainability of the striatal dopaminergic reinnervation and behavioral performances following GDNF washout has important implications. It suggests that GDNF needs to be delivered only transiently to allow prolonged functional regenerative effect, rendering the retrievable capsules attractive to achieve this purpose in PD patients. The promising potential of GDNF to protect and regenerate the nigrostriatal pathway has been hampered by several recent studies showing that long-term GDNF overexpression in the intact nigrostriatal pathway induces a downregulation of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of dopamine. In the last part of this work, we aimed therefore at investigating the effect of GDNF on other enzymes of dopamine biosynthesis, using a lentiviral vector-mediated gene transfer technique, in order to overexpress GDNF in rat striatum. We showed that in addition to TH downregulation, long-term GDNF overexpression results in tetrahydrobiopterin upregulation, and importantly in dopamine decrease in the intact striatum of rats. In a clinical perspective, dose and treatment duration of the trophic factor will thus have to be established and optimized with the aim of achieving beneficial neuroprotective effects while circumventing undesirable pharmacologic effects on dopamine biosynthesis. The discovery of new protective molecules such as the Wlds protein, as well as a better understanding of cellular effects of the promising neurotrophic factor GDNF might lead to the establishment of neuroprotective and neuroregenerative strategies for PD in the close future.