Cerebrospinal fluid protein biomarkers in Parkinson's disease.

Proteomic profiling is an effective way to identify biomarkers for Parkinson's disease (PD). Cerebrospinal fluid (CSF) has direct connectivity with the brain and could be a source of finding biomarkers and their clinical implications. Comparative proteomic profiling has shown that a group of differentially displayed proteins exist. The studies performed using conventional and classical tools also supported the occurrence of these proteins. Many studies have highlighted the potential of CSF proteomic profiling for biomarker identification and their clinical applications. Some of these proteins are useful for disease diagnosis and prediction. Proteomic profiling of CSF also has immense potential to distinguish PD from similar neurodegenerative disorders. A few protein biomarkers help in fundamental knowledge generation and clinical interpretation. However, the specific biomarker of PD is not yet known. The use of proteomic approaches in clinical settings is also rare. A large-scale, multi-centric, multi-population and multi-continental study using multiple proteomic tools is warranted. Such a study can provide valuable, comprehensive and reliable information for a better understanding of PD and the development of specific biomarkers. The current article sheds light on the role of CSF proteomic profiling in identifying biomarkers of PD and their clinical implications. The article also explains the achievements, obstacles and hopes for future directions of this approach.

Deferoxamine Ameliorates Cypermethrin-Induced Iron Accumulation and Associated Alterations.

Iron is widely linked with the onset and development of Parkinson's disease (PD). Accumulation of iron induces free radical generation and promotes α-synuclein aggregation, oxidative stress, and autophagy impairment. Deferoxamine, an iron chelator, is shown to ameliorate iron dyshomeostasis in rodents and humans. However, the role of deferoxamine in cypermethrin-induced iron accumulation is not yet known. Although an iron accumulation and impaired chaperone-mediated autophagy (CMA) contribute to PD, a link between the two is not yet widely understood. Current study is undertaken to explore the possible association between an iron accumulation and CMA in cypermethrin model of PD in the presence of deferoxamine. Level of iron, iron transporter proteins, oxidative stress, and CMA proteins along with indicators of Parkinsonism were measured. Deferoxamine attenuated cypermethrin-induced iron accumulation and number of iron-positive cells and ameliorated the demise of dopaminergic cells and dopamine content. Deferoxamine significantly normalizes cypermethrin-induced changes in iron transporter proteins, α-synuclein, lysosome-associated membrane protein-2A, and oxidative stress. The results demonstrate that deferoxamine ameliorates cypermethrin-induced iron dyshomeostasis and impairment in CMA.

Dyshomeostasis of Iron and Its Transporter Proteins in Cypermethrin-Induced Parkinson's Disease.

The etiology of Parkinson's disease (PD) is highly complex and is still indefinable. However, a number of studies have indicated the involvement of pesticides and transition metals. Copper, magnesium, iron, and zinc have emerged as important metal contributors. Exposure to pesticides causes an accumulation of transition metals in the substantia nigra (SN) region of the brain. The cypermethrin model of PD is characterized by mitochondrial dysfunction, autophagy impairment, oxidative stress, etc. However, the effect of cypermethrin on metal homeostasis is not yet explored. The study was designed to delineate the role of metals and their transporter proteins in cypermethrin-induced animal and cellular models of PD. The level of copper, magnesium, iron, and zinc was checked in the nigrostriatal tissue and serum by atomic absorption spectroscopy. Since cypermethrin consistently increased iron content in the nigrostriatal tissue and serum after 12 weeks of exposure, the level of iron transporter proteins, such as divalent metal transporter-1 (DMT-1), ceruloplasmin, transferrin, ferroportin, and hepcidin, and their in silico interaction with cypermethrin were checked. 3,3'-Diaminobenzidine-enhanced Perl's staining showed an elevated number of iron-positive cells in the SN of cypermethrin-treated rats. Molecular docking studies revealed a strong binding affinity between cypermethrin and iron transporter protein receptors of humans and rats. Furthermore, cypermethrin increased the expression of DMT-1 and hepcidin while reducing the expression of transferrin, ceruloplasmin, and ferroportin in the nigrostriatal tissue and human neuroblastoma cells. These observations suggest that cypermethrin alters the expression of iron transporter proteins leading to iron dyshomeostasis, which could contribute to dopaminergic neurotoxicity.

Exploring the Role of Glycolytic Enzymes PFKFB3 and GAPDH in the Modulation of Aß and Neurodegeneration and Their Potential of Therapeutic Targets in Alzheimer's Disease.

Alzheimer's disease (AD) is presently the 6th major cause of mortality across the globe. However, it is expected to rise rapidly, following cancer and heart disease, as a leading cause of death among the elderly peoples. AD is largely characterized by metabolic changes linked to glucose metabolism and age-induced mitochondrial failure. Recent research suggests that the glycolytic pathway is required for a range of neuronal functions in the brain including synaptic transmission, energy production, and redox balance; however, alteration in glycolytic pathways may play a significant role in the development of AD. Moreover, it is hypothesized that targeting the key enzymes involved in glucose metabolism may help to prevent or reduce the risk of neurodegenerative disorders. One of the major pro-glycolytic enzyme is 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3); it is normally absent in neurons but abundant in astrocytes. Similarly, another key of glycolysis is glyceraldehyde-3-phosphate dehydrogenase (GAPDH) which catalyzes the conversion of aldolase and glyceraldehyde 3 phosphates to 1,3 bisphosphoglycerate. GAPDH has been reported to interact with various neurodegenerative disease-associated proteins, including the amyloid-ß protein precursor (AßPP). These findings indicate PFKFB3 and GAPDH as a promising therapeutic target to AD. Current review highlight the contributions of PFKFB3 and GAPDH in the modulation of Aßand AD pathogenesis and further explore the potential of PFKFB3 and GAPDH as therapeutic targets in AD.

Is Gut Dysbiosis an Epicenter of Parkinson's Disease?

Once recognized as one of the most esoteric diseases of the central nervous system, Parkinson's disease (PD) is now deemed to be a chronic illness contributed by the central, autonomic and enteric nervous systems. Most likely, an accumulation of α-synuclein in the central and enteric nervous systems is the key that supports this viewpoint. Constipation, one of the non-motor hallmarks in roughly two-third of PD patients, is regulated by the composition of gut bacteria, which is assumed to set off the enteric α-synuclein accrual. Vagus nerve is suggested to direct the signal for α-synuclein over-expression and accumulation to the brain. While trillions of microorganisms reside in the intestinal tract, only one third of the proportion inhabits evenly in all individuals. Existence of an impaired gut-microbe-brain axis consonant with dysbiosis could be an epicenter of this inexplicable disorder. Any alteration in the structure and function of the gastrointestinal tract owing to exposure of endogenous or exogenous chemicals or toxicants could lead to dysbiosis. However, inconsistency in the symptoms even after exposure to same chemical or toxicant in PD patients emphatically creates a conundrum. While the level of a few specific neurotransmitters and metabolites is influenced by microbes, implication of dysbiosis is still debatable. Nevertheless, the scientific literature is overflowing with the remarkable observations supporting the role of dysbiosis in PD. Lack of specificity to differentially diagnose PD with non-PD or PD-plus syndrome, to identify highly precise drug targets and to develop therapeutic stratagems to encounter the disease on the basis of this approach, causes us to be open-minded about the dysbiosis theory. The article reviews the facts supporting gut dysbiosis as the foremost trigger for PD onset along with disagreements.

Nanoparticlized System: Promising Approach for the Management of Alzheimer's Disease through Intranasal Delivery.

Alzheimer's disease (AD) is a neurodegenerative brain problem and responsible for causing dementia in aged people. AD has become most common neurological disease in the elderly population worldwide and its treatment remains still challengeable. Therefore, there is a need of an efficient drug delivery system which can deliver the drug to the target site. Nasal drug delivery has been used since prehistoric times for the treatment of neurological disorders like Alzheimer's disease (AD). For delivering drug to the brain, blood brain barrier (BBB) is a major rate limiting factor for the drugs. The desired drug concentration could not be achieved through the conventional drug delivery system. Thus, nanocarrier based drug delivery systems are promising for delivering drug to brain. Nasal route is a most convenient for targeting drug to the brain. Several factors and mechanisms need to be considered for an effective delivery of drug to the brain particularly AD. Various nanoparticlized systems such as nanoparticles, liposomes, exosomes, phytosomes, nanoemulsion, nanosphere, etc. have been recognized as an effective drug delivery system for the management of AD. These nanocarriers have been proven with improved permeability as well as bioavailability of the anti-Alzheimer's drugs. Some novel drug delivery systems of anti-Alzheimer drugs are under investigation of different phase of clinical trials. Present article highlights on the nanotechnology based intranasal drug delivery system for the treatment of Alzheimer's disease. Furthermore, consequences of AD, transportation mechanism, clinical updates and recent patents on nose to brain delivery for AD have been discussed.

Unequivocal Biomarker for Parkinson's Disease: A Hunt that Remains a Pester.

Devastating motor features, lack of early prognostic tools, and absence of undeviating therapies call for an endeavor to develop biomarkers for Parkinson's disease (PD). A biomarker is anticipated to help in timely and selective diagnosis as well as to hunt for an appropriate treatment option. Peripheral fingerprints can be used to assess the progression, distinguish PD from other related disorders, and monitor the efficacy of therapeutic options. From the last two decades, peripheral blood is constantly targeted in search of an appropriate marker owing to minimal invasive procedure for collection, highly dynamic nature, and insignificant ethical concern. Besides, cerebrospinal fluid (CSF) is also preferred because of its close proximity to the brain. Employing conventional and contemporary sophisticated devices, a number of protein and non-protein entities, mainly metallic elements, have been shown to hold adequate potential to be used as biomarkers for monitoring progression and assessing treatment options for such a distressing neurodegenerative disorder. Classical strategies and relatively newer sophisticated tools, such as proteomics, deciphered the presence of an altered level of highly specific blood- and CSF-specific proteins, free metals, metal-binding proteins, common inflammatory proteins, and overexpressed/modified α-synuclein in PD patients. While several chemical entities are shown to be associated, not even a single protein or metal is converted into unambiguous disease fingerprint. The article provides an update on proteins and metals that are shown to possess enormous potential in the course of biomarker exploration but are unable to deliver a reliable indicator. The review also sheds light on the reasons of ineffective hit to hunt for an authentic fingerprint and proposes the doable ways to translate the output into reality.