Research on the signaling pathways related to the intervention of traditional Chinese medicine in Parkinson's disease:A literature review.

ETHNOPHARMACOLOGICAL RELEVANCE: Parkinson's disease (PD) is the most common progressive neurodegenerative disorder affecting more than 10 million people worldwide and is characterized by the progressive loss of Daergic (DA) neurons in the substantia nigra pars compacta. It has been reported that signaling pathways play a crucial role in the pathogenesis of PD, while the active ingredients of traditional Chinese medicine (TCM) have been found to possess a protective effect against PD. TCM has demonstrated significant potential in mitigating oxidative stress (OS), neuroinflammation, and apoptosis of DA neurons via the regulation of signaling pathways associated with PD. AIM OF THE REVIEW: This study discussed and analyzed the signaling pathways involved in the occurrence and development of PD and the mechanism of active ingredients of TCM regulating PD via signaling pathways, with the aim of providing a basis for the development and clinical application of therapeutic strategies for TCM in PD. MATERIALS AND METHODS: With "Parkinson's disease", "Idiopathic Parkinson's Disease", "Lewy Body Parkinson's Disease", "Parkinson's Disease, Idiopathic", "Parkinson Disease, Idiopathic", "Parkinson's disorders", "Parkinsonism syndrome", "Traditional Chinese medicine", "Chinese herbal medicine", "active ingredients", "medicinal plants" as the main keywords, PubMed, Web of Science and other online search engines were used for literature retrieval. RESULTS: PD exhibits a close association with various signaling pathways, including but not limited to MAPKs, NF-κB, PI3K/Akt, Nrf2/ARE, Wnt/ß-catenin, TLR/TRIF, NLRP3, Notch. The therapeutic potential of TCM lies in its ability to regulate these signaling pathways. In addition, the active ingredients of TCM have shown significant effects in improving OS, neuroinflammation, and DA neuron apoptosis in PD. CONCLUSION: The active ingredients of TCM have unique advantages in regulating PD-related signaling pathways. It is suggested to combine network pharmacology and bioinformatics to study the specific targets of TCM. This not only provides a new way for the prevention and treatment of PD with the active ingredients of TCM, but also provides a scientific basis for the selection and development of TCM preparations.

[Resting tremor of Parkinson's disease changing into Holmes' tremor by cerebellar hemorrhage: an examination of the pathophysiological mechanism of tremor].

A 71-year-old male who suffered from Hoehn and Yahr stage III Parkinson's disease with bradykinesia, rigidity and a 5-6-Hz tremor at rest in the right extremities was admitted to our hospital due to the sudden onset of vertigo. Right cerebellar hemorrhage was confirmed by CT. The patient's resting tremor in the right extremities disappeared immediately following the cerebellar hemorrhage. Six days later, MRI showed Wallerian degeneration in the cerebello-rubro-thalamic tract. Approximately 5 months later, a 2-3-Hz Holmes' tremor gradually appeared in the right upper extremity. This tremor was improved by increasing L-dopa doses. Case reports of the disappearance of Parkinson's resting tremor and subsequent emergence of Holmes' tremor due to cerebellar lesion are rare. Furthermore, the Wallerian degeneration of the cerebello-rubro-thalamic tract identified on MRI between tremors of the different frequencies is very rare. We hypothesize that the cause of the tremor frequency change was simultaneous damage to the nigro-striatal network and the cerebello-thalamo-cerebral network.

Towards therapeutic electrophysiological neurofeedback in Parkinson's disease.

Neurofeedback (NF) techniques support individuals to self-regulate specific features of brain activity, which has been shown to impact behavior and potentially ameliorate clinical symptoms. Electrophysiological NF (epNF) may be particularly impactful for patients with Parkinson's disease (PD), as evidence mounts to suggest a central role of pathological neural oscillations underlying symptoms in PD. Exaggerated beta oscillations (12-30 Hz) in the basal ganglia-cortical network are linked to motor symptoms (e.g., bradykinesia, rigidity), and beta is reduced by successful therapy with dopaminergic medication and Deep Brain Stimulation (DBS). PD patients also experience non-motor symptoms related to sleep, mood, motivation, and cognitive control. Although less is known about the mechanisms of non-motor symptoms in PD and how to successfully treat them, low frequency neural oscillations (1-12 Hz) in the basal ganglia-cortical network are particularly implicated in non-motor symptoms. Here, we review how cortical and subcortical epNF could be used to target motor and non-motor specific oscillations, and potentially serve as an adjunct therapy that enables PD patients to endogenously control their own pathological neural activities. Recent studies have demonstrated that epNF protocols can successfully support volitional control of cortical and subcortical beta rhythms. Importantly, this endogenous control of beta has been linked to changes in motor behavior. epNF for PD, as a casual intervention on neural signals, has the potential to increase understanding of the neurophysiology of movement, mood, and cognition and to identify new therapeutic approaches for motor and non-motor symptoms.

Phototherapy for age-related brain diseases: Challenges, successes and future.

Brain diseases present a significant obstacle to both global health and economic progress, owing to their elusive pathogenesis and the limited effectiveness of pharmaceutical interventions. Phototherapy has emerged as a promising non-invasive therapeutic modality for addressing age-related brain disorders, including stroke, Alzheimer's disease (AD), and Parkinson's disease (PD), among others. This review examines the recent progressions in phototherapeutic interventions. Firstly, the article elucidates the various wavelengths of visible light that possess the capability to penetrate the skin and skull, as well as the pathways of light stimulation, encompassing the eyes, skin, veins, and skull. Secondly, it deliberates on the molecular mechanisms of visible light on photosensitive proteins, within the context of brain disorders and other molecular pathways of light modulation. Lastly, the practical application of phototherapy in diverse clinical neurological disorders is indicated. Additionally, this review presents novel approaches that combine phototherapy and pharmacological interventions. Moreover, it outlines the limitations of phototherapeutics and proposes innovative strategies to improve the treatment of cerebral disorders.

Gut microbiota-associated taurine metabolism dysregulation in a mouse model of Parkinson's disease.

IMPORTANCE: PD is recognized as a multisystem disease concerning GI dysfunction and microbiota dysbiosis but still lacks ideal therapies. Recently, aberrant microbiota-derived metabolites are emerging as important participants in PD etiology. However, the alterations of gut microbiota community and serum untargeted metabolite profile have not been fully investigated in a PD mice model. Here, we discover sharply reduced levels of Lactobacillus and taurine in MPTP-treated mice. Moreover, Lactobacillus, Adlercreutzia, and taurine-related metabolites showed the most significant correlation with pathological and GI performance of PD mice. The abundances of microbial transporter and enzymes participating in the degeneration of taurine were disturbed in PD mice. Most importantly, taurine supplement ameliorates MPTP-induced motor deficits, DA neuron loss, and microglial activation. Our data highlight the impaired taurine-based microbiome-metabolism axis during the progression of PD and reveal a novel and previously unrecognized role of genera in modulating taurine metabolism.

Therapeutic considerations of bioactive compounds in Alzheimer's disease and Parkinson's disease: Dissecting the molecular pathways.

Leading neurodegenerative diseases Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by the impairment of memory and motor functions, respectively. Despite several breakthroughs, there exists a lack of disease-modifying treatment strategies for these diseases, as the available drugs provide symptomatic relief and bring along side effects. Bioactive compounds are reported to bear neuroprotective properties with minimal toxicity, however, a detailed elucidation of their modes of neuroprotection is lacking. The review elucidates the neuroprotective mechanism(s) of some of the major phyto-compounds in pre-clinical and clinical studies of AD and PD to understand their potential in combating these diseases. Curcumin, eugenol, resveratrol, baicalein, sesamol and so on have proved efficient in countering the pathological hallmarks of AD and PD. Curcumin, resveratrol, caffeine and so on have reached the clinical phases of these diseases, while aromadendrin, delphinidin, cyanidin and xanthohumol are yet to be extensively explored in pre-clinical phases. The review highlights the need for extensive investigation of these compounds in the clinical stages of these diseases so as to utilize their disease-modifying abilities in the real field of treatment. Moreover, poor pharmacokinetic properties of natural compounds are constraints to their therapeutic yields and this review suggests a plausible contribution of nanotechnology in overcoming these limitations.

Bear bile powder alleviates Parkinson's disease-like behavior in mice by inhibiting astrocyte-mediated neuroinflammation.

Parkinson's disease (PD) is a common neurodegenerative disease in middle-aged and elderly people. In particular, increasing evidence has showed that astrocyte-mediated neuroinflammation is involved in the pathogenesis of PD. As a precious traditional Chinese medicine, bear bile powder (BBP) has a long history of use in clinical practice. It has numerous activities, such as clearing heat, calming the liver wind and anti-inflammation, and also exhibits good therapeutic effect on convulsive epilepsy. However, whether BBP can prevent the development of PD has not been elucidated. Hence, this study was designed to explore the effect and mechanism of BBP on suppressing astrocyte-mediated neuroinflammation in a mouse model of PD. PD-like behavior was induced in the mice by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (30 mg·kg-1) for five days, followed by BBP (50, 100, and 200 mg·kg-1) treatment daily for ten days. LPS stimulated rat C6 astrocytic cells were used as a cell model of neuroinflammation. THe results indicated that BBP treatment significantly ameliorated dyskinesia, increased the levels of tyrosine hydroxylase (TH) and inhibited astrocyte hyperactivation in the substantia nigra (SN) of PD mice. Furthermore, BBP decreased the protein levels of glial fibrillary acidic protein (GFAP), cyclooxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS), and up-regulated the protein levels of takeda G protein-coupled receptor 5 (TGR5) in the SN. Moreover, BBP significantly activated TGR5 in a dose-dependent manner, and decreased the protein levels of GFAP, iNOS and COX2, as well as the mRNA levels of GFAP, iNOS, COX2, interleukin (IL) -1ß, IL-6 and tumor necrosis factor-α (TNF-α) in LPS-stimulated C6 cells. Notably, BBP suppressed the phosphorylation of protein kinase B (AKT), inhibitor of NF-κB (IκBα) and nuclear factor-κB (NF-κB) proteins in vivo and in vitro. We also observed that TGR5 inhibitor triamterene attenuated the anti-neuroinflammatory effect of BBP on LPS-stimulated C6 cells. Taken together, BBP alleviates the progression of PD mice by suppressing astrocyte-mediated inflammation via TGR5.

Recovery of motor function is associated with rescue of glutamate biomarkers in the striatum and motor cortex following treatment with Mucuna pruriens in a murine model of Parkinsons disease.

There is growing interest in the use of natural products for the treatment of Parkinson's disease (PD). Mucuna pruriens has been used in the treatment of humans with PD. The goal of this study was to determine if daily oral treatment with an extract of Mucuna pruriens, starting after the MPTP-induced loss of nigrostriatal dopamine in male mice, would result in recovery/restoration of motor function, tyrosine hydroxylase (TH) protein expression in the nigrostriatal pathway, or glutamate biomarkers in both the striatum and motor cortex. Following MPTP administration, resulting in an 80 % loss of striatal TH, treatment with Mucuna pruriens failed to rescue either striatal TH or the dopamine transporter back to the control levels, but there was restoration of gait/motor function. There was an MPTP-induced loss of TH-labeled neurons in the substantia nigra pars compacta and in the number of striatal dendritic spines, both of which failed to be recovered following treatment with Mucuna pruriens. This Mucuna pruriens-induced locomotor recovery following MPTP was associated with restoration of two striatal glutamate transporter proteins, GLAST (EAAT1) and EAAC1 (EAAT3), and the vesicular glutamate transporter 2 (Vglut2) within the motor cortex. Post-MPTP treatment with Mucuna pruriens, results in locomotor improvement that is associated with recovery of striatal and motor cortex glutamate transporters but is independent of nigrostriatal TH restoration.

Suppression of beta oscillations by delayed feedback in a cortex-basal ganglia-thalamus-pedunculopontine nucleus neural loop model.

Excessive neural synchronization of neural populations in the beta (ß) frequency range (12-35 Hz) is intimately related to the symptoms of hypokinesia in Parkinson's disease (PD). Studies have shown that delayed feedback stimulation strategies can interrupt excessive neural synchronization and effectively alleviate symptoms associated with PD dyskinesia. Work on optimizing delayed feedback algorithms continues to progress, yet it remains challenging to further improve the inhibitory effect with reduced energy expenditure. Therefore, we first established a neural mass model of the cortex-basal ganglia-thalamus-pedunculopontine nucleus (CBGTh-PPN) closed-loop system, which can reflect the internal properties of cortical and basal ganglia neurons and their intrinsic connections with thalamic and pedunculopontine nucleus neurons. Second, the inhibitory effects of three delayed feedback schemes based on the external globus pallidum (GPe) on ß oscillations were investigated separately and compared with those based on the subthalamic nucleus (STN) only. Our results show that all four delayed feedback schemes achieve effective suppression of pathological ß oscillations when using the linear delayed feedback algorithm. The comparison revealed that the three GPe-based delayed feedback stimulation strategies were able to have a greater range of oscillation suppression with reduced energy consumption, thus improving control performance effectively, suggesting that they may be more effective for the relief of Parkinson's motor symptoms in practical applications.

Unveiling Nature's potential: Promising natural compounds in Parkinson's disease management.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta. Although the exact etiology of PD remains elusive, growing evidence suggests a complex interplay of genetic, environmental, and lifestyle factors in its development. Despite advances in pharmacological interventions, current treatments primarily focus on managing symptoms rather than altering the disease's underlying course. In recent years, natural phytocompounds have emerged as a promising avenue for PD management. Phytochemicals derived from plants, such as phenolic acids, flavones, phenols, flavonoids, polyphenols, saponins, terpenes, alkaloids, and amino acids, have been extensively studied for their potential neuroprotective effects. These bioactive compounds possess a wide range of therapeutic properties, including antioxidant, anti-inflammatory, anti-apoptotic, and anti-aggregation activities, which may counteract the neurodegenerative processes in PD. This comprehensive review delves into the pathophysiology of PD, with a specific focus on the roles of oxidative stress, mitochondrial dysfunction, and protein malfunction in disease pathogenesis. The review collates a wealth of evidence from preclinical studies and in vitro experiments, highlighting the potential of various phytochemicals in attenuating dopaminergic neuron degeneration, reducing α-synuclein aggregation, and modulating neuroinflammatory responses. Prominent among the natural compounds studied are curcumin, resveratrol, coenzyme Q10, and omega-3 fatty acids, which have demonstrated neuroprotective effects in experimental models of PD. Additionally, flavonoids like baicalein, luteolin, quercetin, and nobiletin, and alkaloids such as berberine and physostigmine, show promise in mitigating PD-associated pathologies. This review emphasizes the need for further research through controlled clinical trials to establish the safety and efficacy of these natural compounds in PD management. Although preclinical evidence is compelling, the translation of these findings into effective therapies for PD necessitates robust clinical investigation. Rigorous evaluation of pharmacokinetics, bioavailability, and potential drug interactions is imperative to pave the way for evidence-based treatment strategies. With the rising interest in natural alternatives and the potential for synergistic effects with conventional therapies, this review serves as a comprehensive resource for pharmaceutical industries, researchers, and clinicians seeking novel therapeutic approaches to combat PD. Harnessing the therapeutic potential of these natural phytocompounds may hold the key to improving the quality of life for PD patients and moving towards disease-modifying therapies in the future.

Dietary intake of α-ketoglutarate ameliorates α-synuclein pathology in mouse models of Parkinson's disease.

Parkinson's disease (PD) is a progressive movement disorder characterized by dopaminergic (DA) neuron degeneration and the existence of Lewy bodies formed by misfolded α-synuclein. Emerging evidence supports the benefits of dietary interventions in PD due to their safety and practicality. Previously, dietary intake of α-ketoglutarate (AKG) was proved to extend the lifespan of various species and protect mice from frailty. However, the mechanism of dietary AKG's effects in PD remains undetermined. In the present study, we report that an AKG-based diet significantly ameliorated α-synuclein pathology, and rescued DA neuron degeneration and impaired DA synapses in adeno-associated virus (AAV)-loaded human α-synuclein mice and transgenic A53T α-synuclein (A53T α-Syn) mice. Moreover, AKG diet increased nigral docosahexaenoic acid (DHA) levels and DHA supplementation reproduced the anti-α-synuclein effects in the PD mouse model. Our study reveals that AKG and DHA induced microglia to phagocytose and degrade α-synuclein via promoting C1q and suppressed pro-inflammatory reactions. Furthermore, results indicate that modulating gut polyunsaturated fatty acid metabolism and microbiota Lachnospiraceae_NK4A136_group in the gut-brain axis may underlie AKG's benefits in treating α-synucleinopathy in mice. Together, our findings propose that dietary intake of AKG is a feasible and promising therapeutic approach for PD.

Endophytic Fusarium species, a unique bioresource for disaggregator of misfolded alpha-synuclein.

Aggregation of α-synuclein into toxic oligomeric structures has been implicated in the pathogenesis of Parkinson's disease via several key stages of fibrillation, oligomerization, and aggregation. Disaggregation or prevention of aggregation has garnered a lot of attention as a therapeutic strategy to prevent or delay the progression of Parkinson's disease. It has been recently established that certain polyphenolic compounds and catechins present in plants and tea extracts exhibit the potential to inhibit the α-synuclein aggregation. However, their copious supply for therapeutic development is still unsolved. Herein, we report for the first time the disaggregation potential of α-synuclein by an endophytic fungus residing in tea leaves (Camellia sinensis). Briefly, a recombinant yeast expressing α-synuclein was used for pre-screening of 53 endophytic fungi isolated from tea using anti-oxidant activity as a marker for the disaggregation of the protein. One isolate #59CSLEAS exhibited 92.4% reduction in production of the superoxide ions, which were similar to the already established α-synuclein disaggregator, Piceatannol exhibiting 92.8% reduction. Thioflavin T assay further established that #59CSLEAS decreased the oligomerization of α-synuclein by 1.63-fold. Subsequently Dichloro-dihydro-fluorescein diacetate-based fluorescence assay exhibited a reduction in total oxidative stress in the recombinant yeast in the presence of fungal extract, thereby indicating the prevention of oligomerization. Oligomer disaggregation potential of the selected fungal extract was found to be 56.5% as assessed by sandwich ELISA assay. Using morphological as well as molecular methods, the endophytic isolate #59CSLEAS was identified as Fusarium sp. The sequence was submitted in the Genbank with accession number ON226971.1.

Primary motor area-related injury of anterior central gyrus in Parkinson's disease with dyskinesia: A study based on MRS and Q-space.

INTRODUCTION: By using magnetic resonance spectroscopy (MRS) and Q-Space imaging technology, this research analyzes the imaging characteristics of white matter fibers in the primary motor cortex and posterior limbs of the subcortical internal capsule in parkinsonian patients with motor disorders. The correlation among the changes in axonal function and structure in the cerebral cortex and subcortical cortex and motor disorder is further revealed. METHODS: First, motor function and clinical condition of 20 patients with Parkinson's disease is assessed the third section of the Unified Parkinson's Scale and H&Y Parkinson's Clinical Staging Scale. Magnetic resonance (MR) scanning is performed with 1H-MRS. Secondly, the range maps of N-acetylaspartic acid (NAA), Choline (Cho), and Creatine (Cr) in the region of interest (the primary motor area of anterior central cortex gyrus, i.e. M1 region) are obtained, and the ratios of NAA/Cr and Cho are calculated. Third, Q-Space MR diffusion imaging technique is used to collect Q-Space images, and a Dsi-studio workstation is used to post-process the images. The fraction anisotropic (FA), generalized fraction anisotropic (GFA), and apparent diffusion coefficient (ADC) parameters of Q-Space in the primary motor cortex and the region of interest in the posterior limb of the internal capsule are obtained. Finally, the parameters of MRS and Q-Space in the experimental group and the control group are further analyzed by SPSS statistical software. RESULTS: After assessing with Parkinson's score scale, there is obvious motor dysfunction in the experimental group. The average clinical stage of H&Y is 3.0 ± 0.31. In the analysis of MRS data, the ratio of NAA/Cr in the primary motor area of the anterior central gyrus in the experimental group is significantly lower than that in the control group (P < 0.05). In the ADC map obtained by Q-Space imaging technique, the ADC value in the primary motor area of the anterior central gyrus in the experimental group is higher than that in the control group (P < 0.05), and the difference is statistically significant (P < 0.05). There is no significant difference between the experimental group and the control group (P > 0.05) in FA and GFA values of the posterior limb of capsule to characterize the characteristics of white matter fibers. CONCLUSIONS: In parkinsonian patients with motor dysfunction, there are apparent functional and structural changes in the primary motor area neurons and peripheral white matter of the anterior central gyrus, and no obvious damage to the axonal structure of the descending fibers in the cortex.

The Neuroprotective Activities of the Novel Multi-Target Iron-Chelators in Models of Alzheimer's Disease, Amyotrophic Lateral Sclerosis and Aging.

The concept of chelation therapy as a valuable therapeutic approach in neurological disorders led us to develop multi-target, non-toxic, lipophilic, brain-permeable compounds with iron chelation and anti-apoptotic properties for neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), age-related dementia and amyotrophic lateral sclerosis (ALS). Herein, we reviewed our two most effective such compounds, M30 and HLA20, based on a multimodal drug design paradigm. The compounds have been tested for their mechanisms of action using animal and cellular models such as APP/PS1 AD transgenic (Tg) mice, G93A-SOD1 mutant ALS Tg mice, C57BL/6 mice, Neuroblastoma × Spinal Cord-34 (NSC-34) hybrid cells, a battery of behavior tests, and various immunohistochemical and biochemical techniques. These novel iron chelators exhibit neuroprotective activities by attenuating relevant neurodegenerative pathology, promoting positive behavior changes, and up-regulating neuroprotective signaling pathways. Taken together, these results suggest that our multifunctional iron-chelating compounds can upregulate several neuroprotective-adaptive mechanisms and pro-survival signaling pathways in the brain and might function as ideal drugs for neurodegenerative disorders, such as PD, AD, ALS, and aging-related cognitive decline, in which oxidative stress and iron-mediated toxicity and dysregulation of iron homeostasis have been implicated.

Rose essential oil diminishes dopaminergic neuron degenerations and reduces α-synuclein aggregation in Caenorhabditis elegans models of Parkinson's disease.

Parkinson's disease (P.D.) is the second most progressive neurodegenerative disorder in the elderly. Degeneration of dopaminergic (DA) neurons and α-synuclein (α-Syn) accumulated toxicity is the major contributor to this disease. At present, the disease has no effective treatment. Many recent studies focus on identifying novel therapeutics that provide benefits to stop the disease progression in P.D. patients. Screening novel and effective drugs in P.D. animal models is time- and cost-consuming. Rose Essential Oil (REO) extracted from Rosa Rugosa species (R. Setate × R. Rugosa). REO contains Citronellol, Geraniol, and Octadiene that possess anti-Aß, anti-oxidative, and anti-depression-like properties, but no reports have defined the REO effect on P.D. yet. The present study examines the REO neuroprotective potential in transgenic Caenorhabditis elegans P.D. models. We observed that REO reduced α-Syn aggregations and diminished DA neuron degenerations induced by 6-OHDA, reduced food-sensing behavioural disabilities, and prolonged the lifespan of the nematode. Moreover, REO augmented the chymotrypsin-like proteasome and SOD-3 activities. Further, we observed the anti-oxidative role of REO by reducing internal cells ROS. Together, these findings supported REO as an anti-PD drug and may exert its effects by lowering oxidative stress via the anti-oxidative pathway.

Neurodegenerative disorders: From clinicopathology convergence to systems biology divergence.

Neurodegenerative diseases are multifactorial. This means that several genetic, epigenetic, and environmental factors contribute to their emergence. Therefore, for the future management of these highly prevalent diseases, it is necessary to change perspective. If a holistic viewpoint is assumed, the phenotype (the clinicopathological convergence) emerges from the perturbation of a complex system of functional interactions among proteins (systems biology divergence). The systems biology top-down approach starts with the unbiased collection of sets of data generated through one or more -omics techniques and has the aim to identify the networks and the components that participate in the generation of a phenotype (disease), often without any available a priori knowledge. The principle behind the top-down method is that the molecular components that respond similarly to experimental perturbations are somehow functionally related. This allows the study of complex and relatively poorly characterized diseases without requiring extensive knowledge of the processes under investigation. In this chapter, the use of a global approach will be applied to the comprehension of neurodegeneration, with a particular focus on the two most prevalent ones, Alzheimer's and Parkinson's diseases. The final purpose is to distinguish disease subtypes (even with similar clinical manifestations) to launch a future of precision medicine for patients with these disorders.

Reduced power and phase-locking values were accompanied by thalamus, putamen, and hippocampus atrophy in Parkinson's disease with mild cognitive impairment: an event-related oscillation study.

Parkinson's disease (PD) is a multifaceted neurodegenerative disorder accompanied by mild cognitive impairment (MCI) as a crucial nonmotor manifestation. Event-related oscillations (EROs) are suggested to reflect cognitive status associated with subcortical structures in neurodegenerative conditions. In this study, 36 individuals with PD-MCI and 32 PD-CN were compared with 60 healthy control (HC) participants using visual EROs by measures of event-related spectral perturbation and inter-trial coherence, along with subcortical gray matter volumes based on the FIRST algorithm. Cross-correlations among electrophysiological, neuropsychological, and structural parameters were investigated exploratively. Both PD-MCI and PD-CN patients had diminished delta and alpha phase-locking than HC, however, electrophysiological abnormalities were more pronounced in PD-MCI over frontal, central, parietal, and temporal locations in almost all frequency bands, accompanied by bilateral thalamus, hippocampus, and right putamen atrophy. PD-CN had lower hippocampal volumes than HC, without exhibiting any subcortical differences from PD-MCI. Lastly, EROs showed low-to-high correlations with structural and neuropsychological measures. These findings may highlight the complex interplay between electrophysiological, neuropsychological, and structural parameters in detected abnormalities of PD-CN and PD-MCI.

Isoliquiritigenin inhibits microglia-mediated neuroinflammation in models of Parkinson's disease via JNK/AKT/NFκB signaling pathway.

Isoliquiritigenin (ISL) is a flavonoid with numerous pharmacological properties, including anti-inflammation, yet its role in Parkinson's disease (PD) with microglia-mediated neuroinflammation remains unknown. In this study, the effects of ISL on inhibiting microglia-mediated neuroinflammation in PD were evaluated in the 1-methyl-4-phenylpyridinium (MPTP)-induced mouse model of PD and in lipopolysaccharide (LPS)-stimulated BV-2 microglia. Our results showed that ISL prevented behavioral deficits and excessive microglial activation in MPTP-treated mice. Moreover, ISL was found to prevent the elevation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and mitigate the phosphorylation of c-Jun N-terminal protein kinase (JNK), protein kinase B (AKT), nuclear factor kappa light-chain enhancer of activated B cells (NFκB), and inhibitor of NFκB protein ɑ (IκBɑ) in the substantia nigra and striatum of MPTP-treated mice and LPS-stimulated BV-2 cells. Meanwhile, in LPS-stimulated BV-2 cells, ISL inhibited the production of inflammatory mediators such as interleukin (IL)-1ß, IL-6 and tumor necrosis factor alpha (TNF-α). In addition, the agonist of JNK partly abolished the inhibitory effects of ISL in LPS-treated BV-2 cells. Our results demonstrated that ISL inhibits microglia-mediated neuroinflammation in PD models probably through deactivating JNK/AKT/NFκB signaling pathways. The novel findings suggest the therapeutic potential of ISL for microglia-mediated neuroinflammation in PD.

Manganese and related neurotoxic pathways: A potential therapeutic target in neurodegenerative diseases.

Neurodegenerative diseases comprise a group of disorders characterized by progressive loss of neurons over a period of time due to various factors such as oxidative stress, inflammation, accumulation of toxic proteins, excitotoxicity, and metal overexposure. Among those, chronic exposure to manganese (Mn) is known to initiate neurodegeneration resembling extrapyramidal effects like Parkinson's disease (PD). Mn overexposure leads to mitochondrial dysfunction by inhibiting the complexes of electron transport chains (ETC), thus generating oxidative stress (OS). It also alter calcium homeostasis, dysregulate enzyme activity, and an imbalance in neurotransmitters level like dopamine, serotonin etc. Mn in excess convert the monomer form of α-synuclein into oligomers that are toxic to neurons. Furthermore, it increases the exocytosis of misfolded α-synuclein, which activates microglia, chemokines, and proinflammatory cytokines. Despite the critical research and investment, no preventive or disease-modifying treatment has been found because of diverse pathological factors. This review focuses on the pathological involvement of Mn and its mechanistic similarities with various neurodegenerative diseases. Further, the source of Mn exposure, various transporters, and its kinetics inside the human body is compiled. The relationship between Mn overexposure and pathogenesis of PD, Huntington's disease (HD), and Alzheimer's disease (AD) has been discussed. Over and above that, the emerging treatment approaches for Mn toxicity utilizing bioinformatics tools, chelation therapy with calcium ethylenediamine tetra-acetic acid (Ca2+EDTA), para-aminosalicylic acid (PAS), and phytochemicals like flavonoids that are known to rescue neurons from oxidative stress and inflammation are enveloped in the compilation.

Connectivity of the corticostriatal and thalamostriatal systems in normal and parkinsonian states: An update.

The striatum receives abundant glutamatergic afferents from the cortex and thalamus. These inputs play a major role in the functions of the striatal neurons in normal conditions, and are significantly altered in pathological states, such as Parkinson's disease. This review summarizes the current knowledge of the connectivity of the corticostriatal and thalamostriatal pathways, with emphasis on the most recent advances in the field. We also discuss novel findings regarding structural changes in cortico- and thalamostriatal connections that occur in these connections as a consequence of striatal loss of dopamine in parkinsonism.