Experimental Models Of Parkinson's Disease Research Articles

Central treatment of neuropeptide-S attenuates cognitive dysfunction and hippocampal synaptic plasticity impairment by increasing CaMKII/GluR1 in hemiparkinsonian rats.

Neuropeptide-S (NPS) has been demonstrated to mitigate learning and memory deficits in experimental models of Parkinson's Disease (PD). Despite this, the precise mechanisms through which NPS exerts its influence on cognitive functions remain to be fully unknown. This study aims to elucidate the effects of central administration of NPS on learning and memory deficits associated with an experimental rat hemiparkinsonian model, examining both electrophysiological and molecular parameters. The hemiparkinsonian model was established via stereotactic injection of 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle. Central NPS (1 nmol, icv) was administered into the lateral ventricle via a cannula for seven consecutive days following the 6-OHDA lesion. The Morris water maze and object recognition tests were used to evaluate the rat's learning and memory abilities. Long-term potentiation (LTP) recordings were conducted to assess hippocampal synaptic plasticity. Immunohistochemistry was employed to determine the expression levels of phosphorylated CaMKII (pCaMKII), GluR1, and GluR2 in the hippocampus. The 6-OHDA-induced decline in cognitive performance was significantly (p < 0.05) improved in rats that received central NPS. In 6-OHDA-lesioned rats, NPS treatment significantly (p < 0.05) enhanced the amplitude of LTP at the dentate gyrus/perforant path synapses. Furthermore, NPS significantly (p < 0.05) increased the number of pCaMKII and GluR1 immunoreactive cells in the hippocampus, which had been diminished due to 6-OHDA, except for GluR2 levels. These findings provide insight into the mechanisms by which central NPS administration enhances cognitive functions in an experimental model of PD, highlighting its potential therapeutic benefits for addressing cognitive deficits in PD.

A comprehensive review of natural compounds and their structure-activity relationship in Parkinson's disease: exploring potential mechanisms.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopamine-producing cells in the Substantia nigra region of the brain. Complementary and alternative medicine approaches have been utilized as adjuncts to conventional therapies for managing the symptoms and progression of PD. Naturalcompounds have gained attention for their potential neuroprotective effects and ability to target various pathways involved in the pathogenesis of PD. This comprehensive review aims to provide an in-depth analysis of the molecular targets and mechanisms of natural compounds in various experimental models of PD. This review will also explore the structure-activity relationship (SAR) of these compounds and assess the clinical studies investigating the impact of these natural compounds on individuals with PD. The insights shared in this review have the potential to pave the way for the development of innovative therapeutic strategies and interventions for PD.

Orchestrating AMPK/mTOR signaling to initiate melittin-induced mitophagy: A neuroprotective strategy against Parkinson's disease

Apitherapy has a long history in treating Parkinson's disease (PD) in humans, with evidence suggesting that bee venom (BV) can mitigate Parkinson's symptoms. Central to BV's effects is melittin (MLT), a principal peptide whose neuroprotective mechanisms in PD are not fully understood. The study investigated the effects of MLT on an experimental PD model in mice and dopaminergic neuron cells, induced by MPTP or MPP+. We concentrate on the autophagic response elicited by MLT during PD pathogenesis. The findings showed that MLT was shown to protect against MPP+/MPTP cytotoxicity and preserve tyrosine hydroxylase (TH) levels, indicating neuronal safeguarding. Remarkably, MLT instigated mitophagy, enhancing mitochondrial homeostasis in MPP+-exposed SH-SY5Y cells. Further, MLT's promotion of mitophagy was confirmed to be AMPK/mTOR signaling-dependent. Validation using Bafilomycin A1, an autophagy inhibitor, confirmed MLT's neuroprotective role, with autophagy inhibition negating MLT's benefits and reducing TH preservation. These findings illuminate MLT's therapeutic potential, particularly its modulation of mitochondrial dysfunction in PD pathology. Our research advances the understanding of MLT's mechanistic action, emphasizing its role in mitochondrial autophagy and AMPK/mTOR signaling, offering a novel perspective beyond the symptomatic relief associated with BV.

Therapeutic Application of Modulators of Endogenous Cannabinoid System in Parkinson's Disease.

The endogenous cannabinoid system (ECS) of the brain plays an important role in the molecular pathogenesis of Parkinson's disease (PD). It is involved in the formation of numerous clinical manifestations of the disease by regulating the level of endogenous cannabinoids and changing the activation of cannabinoid receptors (CBRs). Therefore, ECS modulation with new drugs specifically designed for this purpose may be a promising strategy in the treatment of PD. However, fine regulation of the ECS is quite a complex task due to the functional diversity of CBRs in the basal ganglia and other parts of the central nervous system. In this review, the effects of ECS modulators in various experimental models of PD in vivo and in vitro, as well as in patients with PD, are analyzed. Prospects for the development of new cannabinoid drugs for the treatment of motor and non-motor symptoms in PD are presented.

The effect of growth hormone on motor findings and dendrite morphology in an experimental Parkinson's disease model.

Approaches for the induction of neurogenesis and neuronal recovery through several modalities are gaining popularity in Parkinson's disease (PD). Growth hormone (GH) seems to have a role in the reversal of neural function following brain injury as well as in normal brain development and function; therefore, the use of GH may represent a feasible strategy in the management of PD. This experimental study aimed to evaluate the effect of growth hormone on motor function and dendrite morphology in rats with 6-hydroxydopamine (6-OHDA)-induced PD model. Thirty-six Sprague Dawley rats were included and randomly allocated into one of the six study groups: two controls and four treatment groups that received daily subcutaneous growth hormone injections for 21days, 1, 2, and 3months. PD model was induced through unilateral 6-OHDA injection to the nigrostriatal pathway. The following assessments were made: apomorphine rotation test, stepping test, and tissue examinations for tyrosine hydroxylase and dendrite morphology. The apomorphine rotation test and the stepping test confirmed the presence of PD. These tests as well as dendritic spine density/number and length assessments showed improvement in PD findings over time with GH administration. Findings of this study suggest that GH administration may improve dendrite morphology and motor function in the PD model, which may translate into symptom relief and quality of life improvement in patients with PD. Such potential benefits should be tested in robust clinical studies.

Immunomodulator-Derived Nanoparticles Induce Neuroprotection and Regulatory T Cell Action to Alleviate Parkinsonism.

Post-translational modification, mitochondrial abruptions, neuroinflammation, and α-synuclein (α-Syn) aggregation are considered as major causes of Parkinson's disease (PD) pathogenesis. The recent literature highlights neuroimmune cross talk and the negative role of immune effector T (Teff) and positive regulation by regulatory T (Treg) cells in PD treatment. Herein, a strategy to endow Treg action paves the path for development of PD treatment. Thus, we explored the neuroprotective efficiency of the immunomodulator and PP2A (protein phosphatase 2) activator, FTY720 nanoparticles in in vivo experimental PD models. Repurposing of FTY720 for PD is known due to its protective effect by reducing PD and its camouflaged role in endowing EZH2-mediated epigenetic regulation of PD. EZH2-FOXP3 interaction is necessary for the neuroprotective Treg cell activity. Therefore, we synthesized FTY720 nanoparticles to improve FTY720 protective efficacy in an in vivo PD model to explore the PP2A mediated signaling. We confirmed the formation of FTY720NPs, and the results of the behavioral and protein expression study showed the significant neuroprotective efficiency of our nanoformulations. In the exploration of neuroprotective mechanism, several lines of evidence confirmed FTY720NPs mediated induction of PP2A/EZH2/FOXP3 signaling in the induction of Treg cells effect in in vivo PD treatment. In summary, our nanoformulations have novel potential to alleviate PD by inducing PP2A-induced epigenetic regulation-mediated neuroimmunomodulation at the clinical setup.

Evaluation of Neuroprotective Activity of Delonix Regia Leaves on Haloperidol Induced Parkinsonism in Experimental Animals

One of the most serious and fatal neurodegenerative disorders, Parkinson disease (PD) is characterized by low levels of dopamine. Reactive oxygen species (ROS) from both endogenous and exogenous sources have a role in the oxidative stress that leads to PD, which is a complex condition. Delo nix Regia is a prominent medicinal plant that is frequently used in Indian systems of medicine. The fruit, leaves, and bark of this plant have been utilised for its antifungal, antiemetic, larvicidal, hepatoprotective, antibacterial, antioxidant, anti-diarrheal, anti-inflammatory, wound-healing, and ant carcinogenic potential, according to Ayurvedic literature. The "antioxidant strategy" is the main topic of this study's therapeutic intervention for Parkinson's disease (PD). The investigation was completed in wistar rats, in which Parkinson’s disease (PD) was induced with haloperidol 2 mg/kg, P.O. The rats were randomly divided into six groups and the test animals received the ethanolic extract of Delo nix regia (DRLE) at a dose of 100, 250 and 500 mg/kg, orally for 15 days. Various behavioural and biochemical parameters were estimated in haloperidol exposed rats. The results of this study conclusively show that Delo nix regia has anti-oxidant activity and neuroprotective activity in haloperidol experimental model of PD.

Impact of alogliptin on lipopolysaccharide-induced experimental Parkinson's disease: Unrevealing neurochemical and histopathological alterations in rodents.

BackgroundDegeneration of the nigrostriatal dopaminergic pathway has been seen as a significant cause of movement disability in Parkinson's disease (PD) patients. However, the exact reason for these degenerative changes has remained obscure. In recent years, incretins have been neuroprotective in various pathologies. In the current study, we have investigated the neuroprotective potential of alogliptin (Alo), a dipeptidyl peptidase-IV (DPP-IV) inhibitor, in a lipopolysaccharide (LPS) induced experimental model of PD. Experimental approachLPS (5μg/5 μl) was infused intranigrally to induce PD in experimental rats. Post-LPS infusion, these animals were treated with Alo for 21 days in three successive dosages of 10, 20, and 40 mg/kg/day/per oral. The study is well supported with the determinations of motor functions biochemical, neurochemical, and histological analysis. Key resultsIntranigral infusion of LPS in rats produced motor deficit. It was accompanied by oxidative stress, elevation in neuroinflammatory cytokines, altered neurochemistry, and degenerative changes in the striatal brain region. While Alo abrogated LPS-induced biochemical/neurochemical alterations, improved motor functions, and preserved neuronal morphology in LPS-infused rats. ConclusionThe observed neuroprotective potential of Alo may be due to its antioxidant and anti-inflammatory actions and its ability to modulate monoaminergic signals. Nonetheless, current findings suggest that improving the availability of incretins through DPP-IV inhibition is a promising strategy for treating Parkinson's disease.

Inspiratory Neural Network Complexity Quantified by Approximate Entropy (ApEn) Analysis in SN 6-OHDA-induced Rat Model of Parkinson’s Disease

Parkinson’s disease (PD) is a multifaceted chronic and progressive neurodegenerative disease that includes a broad range of motor and non-motor symptoms (NMS). Breathing abnormalities are a common NMS in PD, and despite respiratory dysfunction being a major problem in PD as well as respiratory complications being the most common cause of death in PD patients, this NMS receives little attention. Over the last decade, a number of preclinical experimental rat models of PD generated by nigrostriatal site-targeted administration of the neurotoxin 6-hydroxydopamine (6-OHDA) have been used to evaluate various aspects of ventilatory control in PD. While all of these models have been shown to exhibit basal and chemical control of breathing abnormalities that are consistent with those in clinical reports, no studies have assessed the complex intrinsic dynamics that are associated with the central inspiratory neural network in PD. Since preclinical rat models of PD have also been shown exhibit neuroanatomical changes in brainstem regions involved in ventilatory control, it is likely that changes in inspiratory neural network dynamics, which can be assessed using nonlinear dynamical analysis methods, are also present in PD. To begin to assess this possibility, we quantified the complexity of 20 consecutive inspiratory (diaphragm EMG) bursts recorded during basal breathing in urethane-anesthetized spontaneously breathing adult female rats at 4-weeks after unilateral injection of 6-OHDA (n=18) or vehicle (VEH; n=14) directly into the substantia nigra (SN). For these analyses, we calculated approximate entropy (ApEn), which provides a statistical measure of regularity (orderliness) of a signal in the time domain, with values for the embedding dimension m and the tolerance r set to m=3 and r=0.44 SD. ApEn values were significantly higher in 6-OHDA-injected rats compared to VEH-injected rats (0.6169±0.0069 vs 0.5894±0.0087; P=0.017) albeit TI and Tpeak/TI were similar in both groups (TI: 305.8±9.5 vs 300.0±12.7 ms, P=0.713; Tpeak/TI: 51.0±1.3 vs 51.3±1.1%, P=0.904). Other significant differences in temporal features included higher breathing frequencies (93.4±2.4 vs 82.0±3.2 bpm; P=0.007), reduced TE (in ms: 334.7±12.7 vs 445.5±27.4; P=0.001), and decreased inspiratory duty cycle (in %: 47.2±1.1 vs 40.8±2.0; P=0.006) in 6-OHDA (compared to VEH)-injected rats. These observations suggest that respiratory dysfunction in PD is also accompanied by reorganization of the central inspiratory neural network that is associated with greater irregularity or less system order. Additional experiments are needed to identify the precise neural mechanisms underlying this higher system complexity. NIH NS101737; Thomas Hartman Center for Parkinson's Disease Research at Stony Brook University. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Nr1h4 and Thrb ameliorate ER stress and provide protection in the MPTP mouse model of Parkinson's.

Elevated ER stress has been linked to the pathogenesis of several disease conditions including neurodegeneration. In this study, we have holistically determined the differential expression of all the nuclear receptors (NRs) in the presence of classical ER stress inducers. Activation of Nr1h4 and Thrb by their cognate ligands (GW4064 and T3) ameliorates the tunicamycin (TM)-induced expression of ER stress genes. A combination of both ligands is effective in mitigating cell death induced by TM. Further exploration of their protective effects in the Parkinson's disease (PD) model shows that they reduce MPP+-induced dissipation of mitochondrial membrane potential and ROS generation in an in vitro PD model in neuronal cells. Furthermore, the generation of an experimental murine PD model reveals that simultaneous treatment of GW4064 and T3 protects mice from ER stress, dopaminergic cell death, and functional deficits in the MPTP mouse model of PD. Thus, activation of Nr1h4 and Thrb by their respective ligands plays an indispensable role in ER stress amelioration and mounts protective effects in the MPTP mouse model of PD.

Electric activity of the brain at early and late clinical stages of experimental modeling of Parkinson's disease, an impact of hemantane

S. To study an influence of the adamantane derivative hemantane on the electrical activity of the brain structures of mice at the early and late (severe) stages of experimental modeling of Parkinson's disease (PD). For experimental modeling of PD in C57BL/6J mice, 30 male C57BL/6J mice weighing 25-32 g were systemically (intraperitoneally) administered proneurotoxin MPTP in two modes corresponding to different clinical stages of the disease: 1-methyl-4-phenyl-1.2.3.6-tetrahydropyridine (MPTP) at a dose of 12 mg/kg, 4 times and 20 mg/kg, 4 times with an interval of 2 hours, respectively. At the early and late clinical stages of experimental modeling of PD in the brain structures of mice (sensorimotor cortex, substantia nigra, caudate nucleus), EEG desynchronization, an increase in wave amplitude, and an increase in the power spectrum in the range of delta frequencies and beta frequencies are observed at the late symptomatic stage experimental model of PD along with a decrease in electrical activity in the range of 4-12 Hz. Preliminary application of the adamantane derivative hemantane at a dose of 20 mg/kg, both in the early and late clinical stages of PD, prevented an excessive increase in the amplitudes of all groups of waves, normalized theta activity in the range of 4-12 Hz, reduced pathological slowing and dysregulation activity in the ranges delta and beta waves, with the prevalence of these effects in the substantia nigra of the brain of animals. The effect of hemantane is more pronounced at the early clinical stage of experimental modeling of PD than at the later (full-scale) stage.

Coffee and Parkinson's disease.

Parkinson's disease (PD) is a prevalent neurodegenerative disease marked by dopaminergic neuronal loss and misfolded alpha-synuclein (α-syn) accumulation, which results in both motor and cognitive symptoms. Its occurrence grows with age, with a larger prevalence among males. Despite substantial study, effective medicines to reduce or stop the progression of diseases remain elusive. Interest has grown in examining dietary components, such as caffeine present in coffee, for potential medicinal effects. Epidemiological studies imply a lower incidence of PD with coffee drinking, attributable to caffeine's neuroprotective abilities. Beyond caffeine, coffee constituent like chlorogenic acid and cafestol have anti-Parkinsonian benefits. Moreover, coffee use has been related with variations in gut microbiota composition, which may reduce intestinal inflammation and prevent protein misfolding in enteric nerves, perhaps through the microbiota-gut-brain axis. This review gives a summary of the neuroprotective effects of coffee, investigating both its motor and non-motor advantages in individuals with PD as well as in experimental models of PD. We reviewed some bioactive constituents of coffee, their respective interactions with misfolded α-syn accumulation, and its emerging mechanisms associated to the gut microbiome.

Clinical stage Alzheimer’s therapy, NNI‐362 promotes TH+ neurons associated with a reversal of motor deficits in AAV‐alpha synuclein model, leaving alpha synuclein unchanged

AbstractBackgroundNNI‐362 is a novel small molecule identified by phenotypic screening to discover compounds that promote new neurons from human neural progenitor cells and have neuroprotective capacity. A placebo‐controlled, double‐blind Phase 1a trial examined the safety and tolerability of NNI‐362, as well as a pharmacodynamic outcome ‐ the level of plasma p‐tau181, a blood‐based biomarker specific to Alzheimer’s disease (AD) pathology. Results in animal models of other age‐related disorders suggest NNI‐362 has the potential to halt or reverse AD and PD clinically.MethodAn AAV‐alpha synuclein rat model of Parkinson’s disease (PD) (MOTAC, France) was used to examine the effects of NNI‐362 treatment. This model results in anosmia and motor phenotypes, loss of TH+ neurons, and diminished adult‐born neurons triggered by alpha‐synuclein expression in the SNpc. NNI‐362 and placebo were formulated as a lipid suspension and administered orally once daily for up to 6 weeks post‐stabilization of AAV‐synuclein expression. At 8 weeks, brains were removed, and the SNpc sectioned and stained for TH+ neurons, alpha‐synuclein, and BrdU+ adult‐born neurons. Results were compared to AAV‐GFP‐injected, vehicle‐treated rats ‐ in groups of M or F and treatment or placebo (n = 14/group, 7F/7M).ResultBrain permeable therapy NNI‐362 did not alter alpha‐synuclein levels, but promoted BrdU+ neurons in the substantia nigra. Thus, generating and protecting TH+ neurons was associated with reversing motor deficits in females. No motor deficits and no BrdU+ neuron deficits were observed in AAV alpha‐synuclein treated males (twice run model), as such no amelioration by NNI‐362 treatment.ConclusionOral NNI‐362 may be a cause‐agnostic therapeutic ‐ promoting region‐specific new neurons, TH+ neuronal protection, and behavioral improvement when induced by dopaminergic deficit, including neurogenesis deficit. After AAV‐alpha‐synuclein induction of 2 weeks, and then followed by chronic NNI‐362 treatment, both behavior and neuron numbers were no different than AAV‐GFP control levels in this clinically‐relevant experimental model of PD.

The effects of human umbilical cord-derived multipotent mesenchymal stromal cells transplantation in mice of different strains with an experimental model of parkinsonism

One of the promising directions in cell therapy for Parkinson's disease or parkinsonism is the transplantation of multipotent mesenchymal stromal cells from various sources, including human umbilical cord (hUC-MMSCs), the effectiveness of which may depend on the recipient's genotype. Objective. To compare the impact of transplanted MMSC-P on behavior, T-lymphocytes, and macrophages in the brain and lymphoid organs of mice from different lines with a toxic model of parkinsonism. Materials and methods. Adult (6-7 months old) male mice of FVB/N (genotype H-2q) and 129/Sv (genotype H-2b) strains were administered the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at a dose of 30 mg/kg (control group), and after 7 days, hUC-MMSCs (500,000 cells) were transplanted into the tail vein. Behavioral reactions were assessed in open field, rigidity, and rotarod tests. The relative content of T-lymphocytes and activated macrophages in the brain was measured by flow cytometry, and the mass of lymphoid organs was determined. Results. Under the influence of MPTP, the number of rearings, "sniffs into the nest," body length, and step length decreased, the number of boluses increased in FVB/N and 129/Sv mice, and the number of squares crossed in the open field test decreased in 129/Sv mice. In the brain of mice from both lines, the content of activated macrophages increased, and in FVB/N mice, the number of T-lymphocytes also increased. The thymus mass decreased in mice from both lines, while the spleen mass decreased only in 129/Sv mice. The transplantation of hUC-MMSCs improved predominantly motor activity in FVB/N mice, while in 129/Sv mice, emotional activity improved, and manifestations of rigidity decreased in mice from both lines. The content of T-lymphocytes and activated macrophages in the brain of mice from both lines, as well as the thymus mass, corresponded to the values of intact animals. MMSC transplantation promoted the survival of FVB/N and 129/Sv mice with the MPTP-induced parkinsonism model. Conclusions. The manifestations of behavioral disorders, changes in the content of T-lymphocytes and activated macrophages in the brain, and the mass of lymphoid organs in mice with the MPTP-induced parkinsonism model, as well as the positive effects of transplanted hUC-MMSCs in these animals, largely depend on their genotype according to the H-2 system (analogous to the HLA system in humans). The results may provide a basis for developing personalized cell therapy for this pathology using multipotent mesenchymal stromal cells.

Antidyskinetic activity of new derivatives of inydazol-4,5-dicarbonic acid in a parkinsonism experimental model due to administration of 6-hydroxydopapine

BACKGROUND: Levodopa therapy currently remains the clinical method of choice for patients with Parkinsons disease. However, in the late stages of the disease, approximately 80% of patients receiving treatment developed levodopa-induced dyskinesia. The studied substances are derivatives of imidazole-4,5-dicarboxylic acid. Their pharmacological effect is produced due to interaction with the recognition site of NMDA receptor, which, together with their high efficiency, implies that they are safer than previously available drugs in this pharmacological group.&#x0D; AIM: To study the antidyskinetic effect of IEM2295 and IEM2296 derivatives of imidazole-4,5-dicarboxylic acid.&#x0D; MATERIALS AND METHODS: The model is based on the toxic effect of 6-hydroxydopamine on rat brain tissue. The first (control) group of rats received injections of only Levodopa and Benserazide, the second group received injections of Levodopa, Benserazide, and the test substance IEM2295, and the third group received injections of Levodopa, Benserazide and the test substance IEM2296. Each group was evaluated based on three criteria: motor function violations, limb dyskinesia, and axial and chewing dyskinesia. The severity of motor functions was graded on a scale of 0 to 4 points at 35, 70, 105, and 140 minutes after injection of the above substances, where 0 and 4 represent the absence and most pronounced degree of pathological movements, respectively.&#x0D; RESULTS: The result analysis showed that the greatest effect on reducing the severity of limb dyskinesia, axial dyskinesia, and chewing dyskinesia in rats was observed at 105 and 140 minutes after injections of the studied substances. Statistically significant differences between the control group and rats receiving injections of the studied substances were revealed at all the time points for limb dyskinesia; i.e., at 35, 105, and 140 minutes for axial dyskinesia and at 105 and 140 minutes for chewing dyskinesia.&#x0D; CONCLUSIONS: In the experimental model of parkinsonism, IEM2295 and IEM2296 show antiparkinsonian and antidyskinetic activity because they reduce the severity of motor function disorders in rats with levodopa-induced dyskinesia. The results indicate the prospects for continued development of these substances and further research for effective and safe antiparkinsonian agents among compounds of this class.

Tannic Acid Mitigates Rotenone-Induced Dopaminergic Neurodegeneration by Inhibiting Inflammation, Oxidative Stress, Apoptosis, and Glutamate Toxicity in Rats.

Parkinson's disease (PD), a movement disorder, is a neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) region of the brain. The etiopathogenesis of PD involves increased oxidative stress, augmented inflammation, impaired autophagy, accumulation of α-synuclein, and α-Glutamate neurotoxicity. The treatment of PD is limited and there is a lack of agents to prevent the disease/delay its progression and inhibit the onset of pathogenic events. Many agents of natural and synthetic origin have been investigated employing experimental models of PD, mimicking human PD. In the present study, we assessed the effect of tannic acid (TA) in a rodent model of PD induced by rotenone (ROT), a pesticide and an environmental toxin of natural origin reported to cause PD in agricultural workers and farmers. Rotenone (2.5 mg/kg/day, i.p.) was administered for 28 days, and TA (50 mg/kg, orally) was administered 30 min before ROT injections. The study results showed an increase in oxidative stress, as evidenced by the depletion of endogenous antioxidants and enhanced formation of lipid peroxidation products, along with the onset of inflammation following a rise in inflammatory mediators and proinflammatory cytokines. ROT injections have also augmented apoptosis, impaired autophagy, promoted synaptic loss, and perturbed α-Glutamate hyperpolarization in rats. ROT injections also induced the loss of dopaminergic neurons subsequent to the activation of microglia and astrocytes. However, TA treatment was observed to reduce lipid peroxidation, prevent loss of endogenous antioxidants, and inhibit the release and synthesis of proinflammatory cytokines, in addition to the favorable modulation of apoptosis and autophagic pathways. Treatment with TA also attenuated the activation of microglia and astrocytes along with preservation of dopaminergic neurons following reduced loss of dopaminergic neurodegeneration and inhibition of synaptic loss and α-Glutamate cytotoxicity. The effects of TA in ROT-induced PD were attributed to the antioxidant, anti-inflammatory, antiapoptotic, and neurogenesis properties. Based on the present study findings, it can be concluded that TA may be a promising novel therapeutic candidate for pharmaceutical as well as nutraceutical development owing to its neuroprotective properties in PD. Further regulatory toxicology and translational studies are suggested for future clinical usage in PD.

Effect of 6-hydroxydopamine increase the glutathione level in SH-SY5Y human neuroblastoma cells.

Treatment of human neuroblastoma SH-SY5Y cells with a catecholaminergic neurotoxin, 6-hydroxydopamine (6-OHDA) is an acknowledged in vitro experimental model of Parkinson disease (PD). A decrease in the glutathione content occurs in PD. Higher concentrations of 6-OHDA lowered the glutathione level in SH-SY5Y cells, nonetheless, we and other authors found a considerable increase in these cells' glutathione content after 24 h treatment with 60 μM 6-OHDA. A synthetic antioxidant, 4-aminotetramethylpiperidine-1-oxyl (4-AT) exerted a similar effect. The aim of the present study was to explain this surprising effect by monitoring the time course of changes in the levels of reduced (GSH) and oxidized glutathione (GSSG), total antioxidant activity (TAC) of human neuroblastoma cell SH-SY5Y extracts as well as the level of reactive oxygen species and activities of enzymes of glutathione metabolism after treatment of the cells with 60 µM 6-OHDA and/or 4-AT for 30 min - 24 h. A transient decrease in the level of GSH and TAC of cell extracts, increase in the level of GSSG, and decrease in the activities of glutathione peroxidase, glutathione reductase, glutathione S-transferase and γ-glutamyl-cysteine ligase activities were found followed by normalization or overshoot of the GSH level, TAC and enzyme activities. Increased activity of γ-glutamyl-cysteine ligase activity starting after 4-6 h was responsible for the elevation of the level of GSH and TAC in cells treated with 6-OHDA, 4-AT, and both compounds. The 6-OHDA-induced increase in the GSH content is a result of an overcompensatory response. The antioxidant 4-AT may be useful for the induction of an increase in the level of GSH in neural cells, without the negative effect of 6-OHDA.

GSDMD in peripheral myeloid cells regulates microglial immune training and neuroinflammation in Parkinson's disease.

Peripheral bacterial infections without impaired blood-brain barrier integrity have been attributed to the pathogenesis of Parkinson's disease (PD). Peripheral infection promotes innate immune training in microglia and exacerbates neuroinflammation. However, how changes in the peripheral environment mediate microglial training and exacerbation of infection-related PD is unknown. In this study, we demonstrate that GSDMD activation was enhanced in the spleen but not in the CNS of mice primed with low-dose LPS. GSDMD in peripheral myeloid cells promoted microglial immune training, thus exacerbating neuroinflammation and neurodegeneration during PD in an IL-1R-dependent manner. Furthermore, pharmacological inhibition of GSDMD alleviated the symptoms of PD in experimental PD models. Collectively, these findings demonstrate that GSDMD-induced pyroptosis in myeloid cells initiates neuroinflammation by regulating microglial training during infection-related PD. Based on these findings, GSDMD may serve as a therapeutic target for patients with PD.

Intermittent Theta Burst Stimulation Improves Motor and Behavioral Dysfunction through Modulation of NMDA Receptor Subunit Composition in Experimental Model of Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by the progressive degeneration of the dopaminergic system, leading to a variety of motor and nonmotor symptoms. The currently available symptomatic therapy loses efficacy over time, indicating the need for new therapeutic approaches. Repetitive transcranial magnetic stimulation (rTMS) has emerged as one of the potential candidates for PD therapy. Intermittent theta burst stimulation (iTBS), an excitatory protocol of rTMS, has been shown to be beneficial in several animal models of neurodegeneration, including PD. The aim of this study was to investigate the effects of prolonged iTBS on motor performance and behavior and the possible association with changes in the NMDAR subunit composition in the 6-hydroxydopamine (6-OHDA)-induced experimental model of PD. Two-month-old male Wistar rats were divided into four groups: controls, 6-OHDA rats, 6-OHDA + iTBS protocol (two times/day/three weeks) and the sham group. The therapeutic effect of iTBS was evaluated by examining motor coordination, balance, spontaneous forelimb use, exploratory behavior, anxiety-like, depressive/anhedonic-like behavior and short-term memory, histopathological changes and changes at the molecular level. We demonstrated the positive effects of iTBS at both motor and behavioral levels. In addition, the beneficial effects were reflected in reduced degeneration of dopaminergic neurons and a subsequent increase in the level of DA in the caudoputamen. Finally, iTBS altered protein expression and NMDAR subunit composition, suggesting a sustained effect. Applied early in the disease course, the iTBS protocol may be a promising candidate for early-stage PD therapy, affecting motor and nonmotor deficits.

Role of the iNOS isoform in the cardiovascular dysfunctions of male rats with 6-OHDA-induced Parkinsonism

IntroductionAvailable studies have shown the involvement of nitric oxide (NO) in the processes that lead to neurodegeneration in Parkinson's disease (PD). Also, the use of inhibitors of the inducible isoform of NO-synthase (iNOS) promotes neuroprotection and attenuates dopamine (DA) loss in experimental models of Parkinsonism. In addition, NO also appears to be involved in cardiovascular changes in 6-hydroxydopamine (6-OHDA)-induced Parkinsonism. The current study aimed to evaluate the effects of iNOS inhibition on cardiovascular and autonomic function in animals that were subjected to Parkinsonism by the administration of 6-OHDA. Materials and methodsThe animals underwent stereotaxic surgery for bilateral microinfusion of the neurotoxin 6-OHDA (6 mg/mL in 0.2% ascorbic acid in sterile saline solution) or vehicle solution for the Sham group. From the day of stereotaxis until the day of femoral artery catheterization, the animals were treated with the iNOS inhibitor, S-methylisothiourea (SMT; 10 mg/kg; i. p.) or saline solution (0.9%; i. p.) for 7 days. The animals were divided into four groups: Sham-Saline, Sham-SMT, 6-OHDA-Saline, and 6-OHDA-SMT. Subsequent analyses were performed on these four groups. After 6 days, they underwent catheterization of the femoral artery, and 24 h later, mean arterial pressure (MAP) and heart rate (HR) were recorded. Another group of animals (the 6-OHDA and Sham groups) was assessed for aortic vascular reactivity after 7 days of bilateral infusion of 6-OHDA or vehicle, in which cumulative concentration-effect curves (CCEC) were made for phenylephrine (Phenyl), acetylcholine and sodium nitroprusside (NPS). Also, CCEC in the presence of Nw-nitro-arginine-methyl-ester (l-NAME) (10-5 M), SMT (10-6 M), and indomethacin (10-5 M) blockers were made. ResultsThe effectiveness of the 6-OHDA lesion was confirmed with the reduction of DA in 6-OHDA animals. However, treatment with SMT could not reverse the loss of DA. Concerning the baseline parameters, SBP and MAP values were lower in 6-OHDA animals compared to their Sham control, with no effect of treatment with SMT. In the analysis of SBP variability, a decrease in variance, the VLFabs component, and the LFabs component were observed in the 6-OHDA groups when compared to their controls, regardless of treatment with SMT. It was also observed that intravenous injections of SMT resulted in an increase in BP and a decrease in HR. However, the response was not different between the Sham and 6-OHDA groups. In vascular function, there was a hyporeactivity to Phenyl in the 6-OHDA group, and when investigating the mechanisms of this hyporeactivity, it was seen that the Rmax to Phenyl increased with incubation with SMT, indicating that iNOS could be involved in the vascular hyporeactivity of animals with Parkinsonism. ConclusionThus, the set of results presented in this study suggests that part of the cardiovascular dysfunction in animals subjected to 6-OHDA Parkinsonism may be peripheral and involve the participation of endothelial iNOS.