Animal Models Of Parkinson's Disease Research Articles

Respiratory deficits in a female rat model of Parkinson's disease.

What is the central question of this study? How does the 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease model affect the respiratory response in female rats? What effect does ovariectomy have on that response? What is the main finding and its importance? The results suggest a protective effect of ovarian hormones in maintaining normal neuroanatomical integrity of the medullary respiratory nucleus in females. It was observed that ovariectomy alone reduced neurokinin-1 density in the pre-Bötzinger complex and Bötzinger complex, and there was an incremental effect of 6-OHDA and ovariectomy on retrotrapezoid nucleus neurons. Emerging evidence indicates that the course of Parkinson's disease (PD) includes autonomic and respiratory deficiencies in addition to the classical motor symptoms. The prevalence of PD is lower in women, and it has been hypothesized that neuroprotection by ovarian hormones can explain this difference. While male PD animal models present changes in the central respiratory control areas, as well as ventilatory parameters under normoxia and hypercapnia, little is known about sex differences regarding respiratory deficits in this disease background. This study aimed to explore the neuroanatomical and functional respiratory changes in intact and ovariectomized (OVX) female rats subjected to chemically induced PD via a bilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA). The respiratory parameters were evaluated by whole-body plethysmography, and the neuroanatomy was monitored using immunohistochemistry. It was found that dopaminergic neurons in the substantia nigra and neurokinin-1 receptor density in the rostral ventrolateral respiratory group, Bötzinger and pre-Bötzinger complex were reduced in the chemically induced PD animals. Additionally, reduced numbers of Phox2b neurons were only observed in the retrotrapezoid nucleus of PD-OVX rats. Concerning respiratory parameters, in OVX rats, the resting and hypercapnia-induced tidal volume (VT ) is reduced, and ventilation ( ) changes independently of 6-OHDA administration. Notably, there is a reduction in the number of retrotrapezoid nucleus Phox2b neurons and hypercapnia-induced respiratory changes in PD-OVX animals due to a 6-OHDA and OVX interaction. These results suggest a protective effect induced by ovarian hormones in neuroanatomical changes observed in a female experimental PD model.

Pyruvate Prevents Dopaminergic Neurodegeneration and Motor Deficits in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Model of Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopamine(DA)rgic neurons in the substantia nigra of the midbrain, and primarily causes motor symptoms. While the pathological cause of PD remains uncertain, oxidative damage, neuroinflammation, and energy metabolic perturbation have been implicated. Pyruvate has been shown neuroprotective in animal models for many neurological disorders, presumably owing to its potent anti-oxidative, anti-inflammatory, and energy metabolic properties. We therefore investigated whether exogenous pyruvate could also protect nigral DA neurons from degeneration and reverse the associated motor deficits in an animal model of PD using the DA neuron-specific toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP (20mg/kg) was injected four times every 2h into the peritoneum of mice, which resulted in a massive loss of DA neurons as well as an increase in neuronal death and cytosolic labile zinc overload. There were rises in inflammatory and oxidative responses, a drop in the striatal DA level, and the emergence of PD-related motor deficits. In comparison, when sodium pyruvate was administered intraperitoneally at a daily dose of 250mg/kg for 7days starting 2h after the final MPTP treatment, significant relief in the MPTP-induced neuropathology, neurodegeneration, DA depletion, and motor symptoms was observed. Equiosmolar dose of NaCl had no neuroprotective effect, and lower doses of sodium pyruvate did not have any statistically significant effects. These findings suggest that pyruvate has therapeutic potential for the treatment of PD and related neurodegenerative diseases.

Ghrelin Bridges DMV Neuropathology and GI Dysfunction in the Early Stages of Parkinson's Disease.

Ghrelin contributes to the communication between the brain and gastrointestinal (GI) tract. Both decreased ghrelin levels and functional GI disorders are early events in Parkinson's disease (PD) patients and animal models. However, the reason is not clear. Here it is found that choline acetyltransferase (ChAT)‐positive neurons in the dorsal motor nucleus of the vagus nerve (DMV), are lost in PD transgenic mice. In response to the selective damaging of DMV neurons with mu p75‐SAP, a rapid reduction both in plasma total and active ghrelin levels is observed. While by contrast, chemogenetic activation of DMV cholinergic neurons can increase the plasma ghrelin levels. Impairment of cholinergic neurons is accompanied by GI disorders, including decreased stool wet weight, stool dry weight, small intestine advancing rate, and gastric emptying rate, while exogenous ghrelin treatment can partially ameliorate GI dysfunction of A53T α‐synuclein transgenic mice. Using pseudorabies virus retrograde trace method, the existence of a direct pathway from the stomach fundus to the DMV is shown. Taken together, the findings suggest that the reduction in plasma ghrelin levels in the early stages of PD may be the result of the lesion of cholinergic neurons in the DMV, thus linking neurodegeneration and GI dysfunction in PD.

Efficient Sustained-Release Nanoparticle Delivery System Protects Nigral Neurons in a Toxin Model of Parkinson's Disease.

Parkinson’s disease (PD) is a serious neurodegenerative disease wherein the progressive destruction of dopaminergic neurons results in a series of related movement disorders. Effective oral delivery of anti-Parkinson’s drugs is challenging owing to the blood-brain barrier (BBB) and the limited plasma exposure. However, polymeric nanoparticles possess great potential to enhance oral bioavailability, thus improving drug accumulation within the brain. In this work, biodegradable poly(ethylene glycol)-b-poly(trimethylene carbonate) (PEG-PTMC) nanoparticles (PPNPs) were developed to deliver Ginkgolide B (GB) as a potent treatment for PD, aiming to enhance its accumulation within both the blood and the brain. The resultant GB-PPNPs were able to facilitate sustained GB release for 48 h and to protect against 1-methyl-4-phenylpyridine (MPP+)-induced neuronal cytotoxicity without causing any toxic damage. Subsequent pharmacokinetic studies revealed that GB-PPNPs accumulated at significantly higher concentrations in the plasma and brain relative to free GB. Oral GB-PPNP treatment was also linked to desirable outcomes in an animal model of PD, as evidenced by improvements in locomotor activity, levels of dopamine and its metabolites, and tyrosine hydroxylase activity. Together, these data suggest that PPNPs may represent promising tools for the effective remediation of PD and other central nervous system disorders.

Proteomic and Targeted Metabolomic Studies on a Silkworm Model of Parkinson's Disease.

Parkinson's disease (PD) is a chronic and progressive movement disorder that is characterized by the loss of dopaminergic neurons in the brain. Animal models of PD have become very popular in the past two decades to understand the etiology, pathology, and molecular and cellular pathways associated with PD. In this study, we report the first neurotoxin-induced silkworm model for PD by chronic feeding with 6-hydroxydopamine (6-OHDA) and explore the possible molecular mechanisms associated with PD using proteomic and targeted metabolomic approaches. Although silkworm is phylogenetically distant from humans and rats, 6-OHDA treatment produced similar PD phenotypes, including motor dysfunction, dopaminergic neuron degeneration, and decreased levels of dopamine. Major neurotransmitters in the silkworm head tissue were profiled, revealing key molecules implicating neurodegenerative disorder. Proteomics analysis revealed a major downregulation of nearly 50 structural proteins constituting cuticles and microfilaments, indicating mechanical damage in the silkworm tissues. The results suggest that 6-OHDA treatment could induce PD-like symptoms in silkworms and activate similar proteomic and metabolic pathways to those in rats or higher animals. This study demonstrates the feasibility and value of the silkworm-based PD model, which may provide important clues for understanding the molecular and cellular mechanisms underlying PD. The mass spectrometry raw files have been deposited to iProx via the project ID IPX0004206000.

A positive allosteric modulator of mGlu4 receptors restores striatal plasticity in an animal model of l-Dopa-induced dyskinesia

By decreasing glutamate transmission, mGlu4 receptor positive allosteric modulators (mGlu4-PAM), in combination with levodopa (l-DOPA) may restore the synergy between glutamatergic and dopaminergic transmissions, thus maximizing the improvement of motor function in Parkinson's disease (PD). This study aimed to clarify the effects of foliglurax, a selective mGlu4-PAM, on the loss of bidirectional synaptic plasticity associated with l-DOPA-induced dyskinesia (LID). Behavioral assessments compared dyskinesia intensity in 6-hydroxydopamine (6-OHDA)-lesioned rats treated with l-DOPA or l-DOPA plus foliglurax. In slices from the same rats, patch-clamp techniques were used to examine electrophysiological differences in glutamatergic synapses, evaluating the EPSCs mediated by NMDA and AMPA receptors in striatal spiny projection neurons. High-frequency stimulation of corticostriatal fibers was used as long-term potentiation (LTP)-inducing protocol. Conversely, 15 min of low-frequency stimulation was applied to depotentiate LTP. The density of dendritic spines was measured in striatal slices in the same experimental conditions. Our results show that, in corticostriatal slices, foliglurax decreased spontaneous glutamatergic transmission in both sham-operated and 6-OHDA lesioned rats. When co-administered with l-DOPA in 6-OHDA-lesioned rats, foliglurax fully restored dendritic spine density in a dose-dependent manner. Moreover, this co-treatment rescued striatal bidirectional plasticity and attenuated the intensity of l-DOPA-induced dyskinesia. This is the first demonstration in an animal model of PD and dyskinesia that a mGlu4 PAM can restore striatal synaptic plasticity.

4-Phenylbutyrate Mitigates the Motor Impairment and Dopaminergic Neuronal Death During Parkinson's Disease Pathology via Targeting VDAC1 Mediated Mitochondrial Function and Astrocytes Activation.

Parkinson's disease (PD) is a progressive motor neurodegenerative disorder significantly associated with protein aggregation related neurodegenerative mechanisms. In view of no disease modifying drugs, the present study was targeted to investigate the therapeutic effects of pharmacological agent 4-phenylbutyric acid (4PBA) in PD pathology. 4PBA is an FDA approved monocarboxylic acid with inhibitory activity towards histone deacetylase andclinically treats urea cycle disorder. First, we observed the significant protective effects of 4PBA on PD specific neuromuscular coordination, level of tyrosine hydroxylase, α-synuclein level and neurotransmitter dopamine in both substantia nigra and striatal regions of the experimental rat model of PD. Further results revealed that treatment with 4PBA drug exhibited significant protection against disease related oxidative stress and augmented nitrite levels. The disease pathology-related depletion in mitochondrial membrane potential and augmented level of calcium as well as mitochondrion membrane located VDAC1 protein level and cytochrome-c translocation were also significantly attenuated with 4PBA administration. Inhibited neuronal apoptosis and restored neuronal morphology were also observed with 4PBA treatment as measured by level of pro-apoptotic proteins t-Bid, Bax and cleaved caspase-3 along with cresyl violet staining in both substantia nigra and striatal regions. Lastly, PD-linked astrocyte activation was significantly inhibited with 4PBA treatment. Altogether, our findings suggest that 4PBA exerts broad-spectrum neuroprotective effects in PD animal model.

Abrogating Oxidative Stress as a Therapeutic Strategy Against Parkinson's Disease: A Mini Review of the Recent Advances on Natural Therapeutic Antioxidant and Neuroprotective Agents.

Reactive oxygen species (ROS) play a vital role in cell signaling when maintained at low concentrations. However, when ROS production exceeds the neutralizing capacity of endogenous antioxidants, oxidative stress is observed, which has been shown to contribute to neurodegenerative diseases such as Parkinson's disease (PD). PD is a progressive disorder characterized by the loss of dopaminergic neurons from the striatum, which leads to motor and nonmotor symptoms. Although the complex interplay of mechanisms responsible is yet to be fully understood, oxidative stress was found to be positively associated with PD. Despite active research, currently proposed regimens mainly focus on regulating dopamine metabolism within the brain, even though these treatments have shown limited long-term efficacy and several side effects. Due to the implication of oxidative stress in the pathophysiology of PD, natural antioxidant compounds have attracted interest as potential therapeutics over the last years, with a more favorable anticipated safety profile due to their natural origin. Therefore, natural antioxidants are currently being explored as promising anti-PD agents. In this mini-review, emphasis was given to presently studied natural antioxidant and neuroprotective agents that have shown positive results in PD animal models. For this purpose, recent scientific articles were reviewed and discussed, with the aim to highlight the most up-to-date advances on PD treatment strategies related to oxidative stress. A plethora of natural compounds are actively being explored against PD, including kaemferol, icaritin, artemisinin, and α-bisabolol, with promising results. Most of these compounds have shown adequate neuroprotective ability along with redox balance restoration, normalized mitochondrial function, and limitation of oxidative damage. In conclusion, natural antioxidants may be the way forward to novel treatments against PD when the limitations of correct dosing and appropriate combinations are resolved.

Glucagon-like peptide 1 and glucose-dependent insulinotropic peptide hormones and novel receptor agonists protect synapses in Alzheimer's and Parkinson's diseases.

Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are peptide hormones and growth factors. A major pathological feature of both Alzheimer’s dis-ease (AD) and Parkinson’s disease (PD) is the loss of synaptic transmission in the cortex in AD and the loss of dopaminergic synapses in the nigra-striatal dopaminergic projection. Several studies demonstrate that GLP-1 and GIP receptor agonists protect synapses and synaptic transmission from the toxic events that underlie AD and PD. In a range of AD animal models, treatment with GLP-1, GIP, or dual-GLP-1/GIP receptor agonists effectively protected cognition, synaptic trans-mission, long-term potentiation (LTP), and prevented the loss of synapses and neurons. In PD models, dopaminergic production resumed and synapses became functional again. Importantly, the GLP-1 receptor agonists exendin-4 and liraglutide have shown good protective effects in clinical trials in AD and PD patients. Studies show that growth factors and peptide drugs that can cross the blood–brain barrier (BBB) better are more potent than those that do not cross the BBB. We therefore developed dual-GLP-1/GIP receptor agonists that can cross the BBB at an enhanced rate and showed superior protective properties on synapses in animal models of AD and PD.

Epigallocatechin gallate for Parkinson's disease.

In the last couple of decades, we have experienced increased use of nutraceuticals worldwide with a demand for organic foods, which has been elevated to an extent probably unmatched with other periods of our civilization. One of the nutraceuticals that gained attention is epigallocatechin gallate (EGCG), a polyphenol in green tea. It has been suggested that diseases of the central nervous system can benefit from consuming some antioxidants, despite current results showing little evidence for their use in preventing and treating these diseases. ECGC may be beneficial in delaying the neurodegeneration of the substantia nigra regardless of the origin of Parkinson's disease (PD). This review covers the effect of EGCG on vitro and animal models of PD, the potential mechanisms of neuroprotection involved and summaries recent clinical trials in human PD. This review also aims to provide an investigative analysis of the current knowledge in this field and to identify putative crucial issues. Environmental factors such as dietary habits, drug use and social interaction are all factors that influence the evolution of neurodegenerative diseases. Therefore, the use of nutraceuticals requires further investigation.

Effects of obesity on neuroinflammatory and neurochemical parameters in an animal model of reserpine-induced Parkinson's disease

Obesity is associated with low-grade chronic inflammation and oxidative stress, affecting the brain's reward system by decreasing dopaminergic neurotransmission. It is known that dopaminergic neurotransmission is also reduced in Parkinson's disease (PD), and high adiposity is considered a risk factor for the development of several neurodegenerative diseases, including PD. This study aimed to assess the effects of obesity on neuroinflammatory and neurochemical parameters in an animal model of reserpine-induced PD. The obese group showed increased inflammation and oxidative damage as well as inhibition of mitochondrial respiratory chain complexes I and II and DNA damage in the evaluated structures. The PD group did not show inflammation or mitochondrial dysfunction but exhibited oxidative damage in the hippocampus. The combination group (obesity + PD) showed reduced inflammation and oxidative stress and increased activity of complexes I and II of the mitochondrial respiratory chain in most of the analyzed structures. On the other hand, obesity + PD caused oxidative damage to proteins in the liver, prefrontal cortex, striatum, and cerebral cortex and oxidative stress in the hypothalamus, resulting in reduced catalase activity. Furthermore, the combination group showed DNA damage in blood, liver, and cerebral cortex. In conclusion, it was observed that the association of obesity and PD did not increase inflammation, oxidative stress, or mitochondrial dysfunction in most of the evaluated structures but increased oxidative damage and induced mechanisms that led to DNA damage in peripheral tissues and brain structures.

Nitric Oxide Involvement in Cardiovascular Dysfunctions of Parkinson Disease.

Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra, causing motor changes. In addition to motor symptoms, non-motor dysfunctions such as psychological, sensory and autonomic disorders are recorded. Manifestations related to the autonomic nervous system include the cardiovascular system, as postural hypotension, postprandial hypotension, and low blood pressure. One of the mediators involved is the nitric oxide (NO). In addition to the known roles such as vasodilator, neuromodulator, NO acts as an important mediator of the immune response, increasing the inflammatory response provoked by PD in central nervous system. The use of non-specific NOS inhibitors attenuated the neurodegenerative response in animal models of PD. However, the mechanisms by which NO contributes to neurodegeneration are still not well understood. The literature suggest that the contribution of NO occurs through its interaction with superoxides, products of oxidative stress, and blocking of the mitochondrial respiratory chain, resulting in neuronal death. Most studies involving Parkinsonism models have evaluated brain NO concentrations, with little data available on its peripheral action. Considering that studies that evaluated the involvement of NO in the neurodegeneration in PD, through NOS inhibitors administration, showed neuroprotection in rats, it has prompted new studies to assess the participation of NOS isoforms in cardiovascular changes induced by parkinsonism, and thus to envision new targets for the treatment of cardiovascular disorders in PD. The aim of this study was to conduct a literature review to assess available information on the involvement of nitric oxide (NO) in cardiovascular aspects of PD.

Lippia grata essential oil complexed with β-cyclodextrin ameliorates biochemical and behavioral deficits in an animal model of progressive parkinsonism.

Parkinson's disease (PD) is identified by the loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc), and is correlated to aggregates of proteins such as α-synuclein, Lewy's bodies. Although the PD etiology remains poorly understood, evidence suggests a main role of oxidative stress on this process. Lippia grata Schauer, known as "alecrim-do-mato", "alecrim-de-vaqueiro", "alecrim-da-chapada", is a native bush from tropical areas mainly distributed throughout the Central and South America. This plant species is commonly used in traditional medicine for relief of pain and inflammation conditions, and that has proven antioxidant effects. We evaluated the effects of essential oil of the L. grata after its complexed with β-cyclodextrin (LIP) on PD animal model induced by reserpine (RES). Behavioral assessments were performed across the treatment. Upon completion the treatment, the animals were euthanized, afterwards their brains were isolated and processed for immunohistochemical and oxidative stress analysis. The LIP treatment delayed the onset of the behavior of catalepsy, decreased the number of oral movements and prevented the memory impairment on the novel object recognition task. In addition, the treatment with LIP protected against dopaminergic depletion in the SNpc and dorsal striatum (STRd), and decreased the α-syn immunoreactivity in the SNpc and hippocampus (HIP). Moreover, there was reduction of the oxidative stability index. These findings demonstrated that the LIP treatment has neuroprotective effect in a progressive parkinsonism model, suggesting that LIP could be an important source for novel treatment approaches in PD.

Quantifying Viscous Damping and Stiffness in Parkinsonism Using Data-Driven Model Estimation and Admittance Control.

Rigidity of upper and lower limbs in Parkinson's disease (PD) is typically assessed via a clinical rating scale that is subject to human perception biases. Methodologies to quantify changes in rigidity associated with the angular position (stiffness) or velocity (viscous damping) are needed to enhance our understanding of PD pathophysiology and objectively assess therapies. In this proof of concept study, we developed a robotic system and a model-based approach to estimate viscous damping and stiffness of the elbow. Our methodology enables the subject to freely rotate the elbow using an admittance controller while torque perturbations tailored to identify the arm dynamics are delivered. The viscosity and stiffness are calculated based on the experimental data using least-squares estimation. We validated our technique using computer simulations and experiments with a nonhuman animal model of PD in the presence and absence of deep brain stimulation therapy. Our data show that stiffness and viscosity measurements can better differentiate rigidity changes than scores previously used for research, including the work and impulse scores, and the modified unified Parkinson's disease rating scale. Our estimation method is suitable for quantifying the effect of therapies on viscous damping and stiffness and studying the pathophysiological mechanisms underlying rigidity in PD.

Testosterone propionate improves motor alterations and dopaminergic damage in the reserpine-induced progressive model of Parkinson's disease

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder with a higher susceptibility to occur in men. Studies suggest that this susceptibility is related to the hormonal differences observed between men and women, being a risk factor for PD. In addition, testosterone supplementation has shown controversial results in animal models of PD and parkinsonian patients. This study evaluated the effect of chronic administration of testosterone propionate (TP) on motor behavior and neurochemical parameters in the reserpine-induced rat model of parkinsonism. Male Wistar rats received 15 injections of reserpine (RES – 0.1 mg/kg) every other day and were concomitantly treated with different doses (0.1, 1.0, or 5.0 mg/kg) of daily TP for 30 days. The rats were euthanized 48 h after the 15th injection of RES or vehicle. Brains were removed and subjected to Tyrosine hydroxylase (TH) immunohistochemistry. TP at 1.0 mg/kg reduced the damages caused by reserpine in the vacuous chewing and tong protrusion behaviors and prevented dopaminergic damage in the SNpc, VTA, and Striatum. TP at 5.0 mg/kg reduced the damages caused by reserpine in the catalepsy and tong protrusion behaviors, prevented the weight loss, and prevented dopaminergic damage in the VTA. Our results suggest that chronic administration of TP has a protective effect in a rat model of parkinsonism, improving motor alterations and dopamine depletion induced by RES.

Enteric glial cell reactivity in colonic layers and mucosal modulation in a mouse model of Parkinson’s disease induced by 6-hydroxydopamine

Enteric glial cells (EGCs) constitute the majority of the neural population of the enteric nervous system and are found in all layers of the gastrointestinal tract. It is active in enteric functions such as immunomodulation, participating in inflammation and intestinal epithelial barrier (IEB) regulation. Both EGCs and IEB have been described as altered in Parkinson's disease (PD). Using an animal model of PD induced by 6-hydroxydopamine (6-OHDA), we investigated the effect of ongoing neurodegeneration on EGCs and inflammatory response during short periods after model induction. C57Bl/6 male mice were unilaterally injected with 6-OHDA in the striatum. Compared to the control group, 6-OHDA animals showed decreased relative water content in their feces from 1 w after model induction. Moreover, at 1 and 2 w post-induction, groups showed histopathological changes indicative of intestinal inflammation. We identified an increase in IBA1 and GFAP levels in the intestinal mucosa. At an earlier survival of 48 h, we detected an increase in GFAP in the neuromuscular layer, suggesting that it was a primary event for the upregulation of GDNF, TNF-α, and occludin in the intestinal mucosa observed after 1 w. Within 2 w, we identified a decrease in the expression of occludin barrier proteins. Thus, EGCs modulation may be an early enteric signal induced by parkinsonian neurodegeneration, followed by inflammatory and dysmotility signs besides IEB modification.

GLP-1 Receptor Agonists in Neurodegeneration: Neurovascular Unit in the Spotlight.

Defects in brain energy metabolism and proteopathic stress are implicated in age-related degenerative neuronopathies, exemplified by Alzheimer’s disease (AD) and Parkinson’s disease (PD). As the currently available drug regimens largely aim to mitigate cognitive decline and/or motor symptoms, there is a dire need for mechanism-based therapies that can be used to improve neuronal function and potentially slow down the underlying disease processes. In this context, a new class of pharmacological agents that achieve improved glycaemic control via the glucagon-like peptide 1 (GLP-1) receptor has attracted significant attention as putative neuroprotective agents. The experimental evidence supporting their potential therapeutic value, mainly derived from cellular and animal models of AD and PD, has been discussed in several research reports and review opinions recently. In this review article, we discuss the pathological relevance of derangements in the neurovascular unit and the significance of neuron–glia metabolic coupling in AD and PD. With this context, we also discuss some unresolved questions with regard to the potential benefits of GLP-1 agonists on the neurovascular unit (NVU), and provide examples of novel experimental paradigms that could be useful in improving our understanding regarding the neuroprotective mode of action associated with these agents.

Advances in Parkinson's disease induced by α-synuclein transmitted through the gut-brain axis

Parkinson's disease (PD) is the most common neurodegenerative disease. Along with the population aging of China, the increase of PD patients in China will result in serious economic and medical burdens. The typical pathological characteristics of PD are the death of dopaminergic neurons in the substantia nigra compacta and the pathological inclusion bodies formed by abnormally aggregated amyloid alpha-synuclein (α-Syn) in dopaminergic neurons, which is also named as Lewy body. Studies have found that the Lewy body exists not only in the central nervous system, but also in the peripheral nervous system. The abundant enteric nervous system in the gut is called the "second brain". The discovery of the gut-brain axis also proves that α-Syn can be transmitted bilaterally between the brain and the gut. The gut microbiota was shown to be involved in the formation and transmission of pathological α-Syn. Therefore, this article summarized the bilateral transmission relationship of α-Syn in the brain and the gut and illustrated the influence of gut microbiota on the abnormal aggregation of α-Syn. Combined with the current progresses on PD patients and animal models especially the non-human primate experiments, this article aimed to provide a reference for the screening and diagnosis of PD.

Gut Microbiota: A Novel Therapeutic Target for Parkinson's Disease.

Parkinson’s disease (PD) is the second most common neurodegenerative disease characterized by motor dysfunction. Growing evidence has demonstrated that gut dysbiosis is involved in the occurrence, development and progression of PD. Numerous clinical trials have identified the characteristics of the changed gut microbiota profiles, and preclinical studies in PD animal models have indicated that gut dysbiosis can influence the progression and onset of PD via increasing intestinal permeability, aggravating neuroinflammation, aggregating abnormal levels of α-synuclein fibrils, increasing oxidative stress, and decreasing neurotransmitter production. The gut microbiota can be considered promising diagnostic and therapeutic targets for PD, which can be regulated by probiotics, psychobiotics, prebiotics, synbiotics, postbiotics, fecal microbiota transplantation, diet modifications, and Chinese medicine. This review summarizes the recent studies in PD-associated gut microbiota profiles and functions, the potential roles, and mechanisms of gut microbiota in PD, and gut microbiota-targeted interventions for PD. Deciphering the underlying roles and mechanisms of the PD-associated gut microbiota will help interpret the pathogenesis of PD from new perspectives and elucidate novel therapeutic strategies for PD.

Acupuncture Regulates Symptoms of Parkinson's Disease via Brain Neural Activity and Functional Connectivity in Mice.

Parkinson’s disease (PD) is a multilayered progressive brain disease characterized by motor dysfunction and a variety of other symptoms. Although acupuncture has been used to ameliorate various symptoms of neurodegenerative disorders, including PD, the underlying mechanisms are unclear. Here, we investigated the mechanism of acupuncture by revealing the effects of acupuncture treatment on brain neural responses and its functional connectivity in an animal model of PD. We observed that destruction of neuronal network between many brain regions in PD mice were reversed by acupuncture. Using machine learning analysis, we found that the key region associated with the improvement of abnormal behaviors might be related to the neural activity of M1, suggesting that the changes of c-Fos in M1 could predict the improvement of motor function induced by acupuncture treatment. In addition, acupuncture treatment was shown to significantly normalize the brain neural activity not only in M1 but also in other brain regions related to motor behavior (striatum, substantia nigra pars compacta, and globus pallidus) and non-motor symptoms (hippocampus, lateral hypothalamus, and solitary tract) of PD. Taken together, our results demonstrate that acupuncture treatment might improve the PD symptoms by normalizing the brain functional connectivity in PD mice model and provide new insights that enhance our current understanding of acupuncture mechanisms for non-motor symptoms.