Mechanistic correlation of molecular pathways in obesity-mediated stroke pathogenesis.

Obesity, a prominent risk factor for the development of heart attacks and several cardiovascular ailments. Obesity ranks as the second most significant avoidable contributor to mortality, whereas stroke stands as the second leading cause of death on a global scale. While changes in lifestyle have been demonstrated to have significant impacts on weight management, the long-term weight loss remains challenging, and the global prevalence of obesity continues to rise. The pathophysiology of obesity has been extensively studied during the last few decades, and an increasing number of signal transduction pathways have been linked to obesity preclinically. This review is focused on signaling pathways, and their respective functions in regulating the consumption of fatty food as well as accumulation of adipose tissue, and the resulting morphological and cognitive changes in the brain of individuals with obesity. We have also emphasized the recent progress in the mechanisms behind the emergence of obesity, as elucidated by both experimental and clinical investigations. The mounting understanding of signaling transduction may shed light on the future course of obesity research as we move into a new era of precision medicine.

Glycosylation: A new signaling paradigm for the neurovascular diseases.

A wide range of life-threatening conditions with complicated pathogenesis involves neurovascular disorders encompassing Neurovascular unit (NVU) damage. The pathophysiology of NVU is characterized by several features including tissue hypoxia, stimulation of inflammatory and angiogenic processes, and the initiation of intricate molecular interactions, collectively leading to an elevation in blood-brain barrier permeability, atherosclerosis and ultimately, neurovascular diseases. The presence of compelling data about the significant involvement of the glycosylation in the development of diseases has sparked a discussion on whether the abnormal glycosylation may serve as a causal factor for neurovascular disorders, rather than being just recruited as a secondary player in regulating the critical events during the development processes like embryo growth and angiogenesis. An essential tool for both developing new anti-ischemic therapies and understanding the processes of ischemic brain damage is undertaking pre-clinical studies of neurovascular disorders. Together with the post-translational modification of proteins, the modulation of glycosylation and its enzymes implicates itself in several abnormal activities which are known to accelerate neuronal vasculopathy. Despite the failure of the majority of glycosylation-based preclinical and clinical studies over the past years, there is a significant probability to provide neuroprotection utilizing modern and advanced approaches to target abnormal glycosylation activity at embryonic stages as well. This article focuses on a variety of experimental evidence to postulate the interconnection between glycosylation and vascular disorders along with possible treatment options.

Mechanistic Implications of GSK and CREB Crosstalk in Ischemia Injury.

Ischemia-reperfusion (IR) injury is a damage to an organ when the blood supply is less than the demand required for normal functioning, leading to exacerbation of cellular dysfunction and death. IR injury occurs in different organs like the kidney, liver, heart, brain, etc., and may not only involve the ischemic organ but also cause systemic damage to distant organs. Oxygen-glucose deprivation in cells causes oxidative stress, calcium overloading, inflammation, and apoptosis. CREB is an essential integrator of the body's various physiological systems, and it is widely accepted that dysfunction of CREB signaling is involved in many diseases, including ischemia-reperfusion injury. The activation of CREB can provide life to a cell and increase the cell's survival after ischemia. Hence, GSK/CREB signaling pathway can provide significant protection to cells of different organs after ischemia and emerges as a futuristic strategy for managing ischemia-reperfusion injury. Different signaling pathways such as MAPK/ERK, TLR4/MyD88, RISK, Nrf2, and NF-κB, get altered during IR injury by the modulation of GSK-3 and CREB (cyclic AMP response element (CRE)-binding protein). GSK-3 (protein kinase B) and CREB are the downstream targets for fulfilling the roles of various signaling pathways. Calcium overloading during ischemia increases the expression of calcium-calmodulin-dependent protein kinase (CaMK), which subsequently activates CREB-mediated transcription, thus promoting the survival of cells. Furthermore, this review highlights the crosstalk between GSK-3 and CREB, promoting survival and rendering the cells resistant to subsequent severe ischemia.

Nuclear orphan receptors: A novel therapeutic agent in neuroinflammation.

Orphan receptors constitute a historically varied subsection of a superfamily of nuclear receptors. Nuclear receptors regulate gene expression in response to ligand signals and are particularly alluring therapeutic targets for chronic illnesses. Neuroinflammation and neurodegenerative diseases have been linked to these orphan nuclear receptors. Preclinical and clinical evidence suggests that orphan receptors could serve as future targets in neuroinflammation, such as Parkinson's disease (PD), Alzheimer's Disease (AD), Huntington's Disease (HD), Multiple Sclerosis (MS), and Cerebral Ischemia. Given the therapeutic relevance of certain orphan receptors in a variety of disorders, their potential in neuroinflammation remains unproven. There is substantial evidence that ligand-activated transcription factors have great promise for preventing neurodegenerative and neurological disorders, with certain orphan nuclear receptors i.e., PPARγ, NR4As, and orphan GPCRs holding particularly high potential. Based on previous findings, we attempted to determine the contribution of PPAR, NR4As, and orphan GPCRs-regulated neuroinflammation to the pathogenesis of these disorders and their potential to become novel therapeutic targets.

Pharmacological modulation of HIF-1 in the treatment of neuropsychiatric disorders.

Hypoxia-inducible factor 1 has been identified as an important therapeutic target in psychiatric illnesses. Hypoxia is a condition in which tissues do not receive enough oxygen, resulting in less oxidative energy production. HIF-1, the master regulator of molecular response to hypoxia, is destabilized when oxygen levels fall. HIF-1, when activated, increases the gene transcription factors that promote adaptive response and longevity in hypoxia. HIF-regulated genes encode proteins involved in cell survival, energy metabolism, angiogenesis, erythropoiesis, and vasomotor control. Multiple genetic and environmental variables contribute to the pathophysiology of psychiatric disease. This review focuses on the most recent findings indicating the role of oxygen deprivation in CNS damage, with strong attention on HIF-mediated pathways. Several pieces of evidence suggested that, in the case of hypoxia, induction and maintenance of HIF-1 target genes may help reduce nerve damage. Major new insights into the molecular mechanisms that control HIF's sensitivity to oxygen are used to make drugs that can change the way HIF works as a therapeutic target for some CNS diseases.

Molecular Complex of HSIM-loaded Polymeric Nanoparticles: Potential Carriers in Osteoporosis.

BACKGROUND: Statins, especially simvastatin promote bone formation by stimulating the activity of osteoblasts and suppressing osteoclast activity via the BMP-Smad signaling pathway. Statins present the liver first-pass metabolism. This study attempts to fabricate and evaluate simvastatin functionalized hydroxyapatite encapsulated in poly(lactic-co-glycolic) acid (PLGA) nanoparticles (HSIM-PLGA NPs) administered subcutaneously with sustained release properties for effective management of osteoporosis. METHODS: Simvastatin functionalized hydroxyapatite (HSIM) was prepared by stirring and validated by docking studies, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and X-ray diffraction (XRD). Further, HSIM-loaded PLGA nanoparticles (HSIM-PLGA NPs) were developed via the solvent emulsification method. The nanoparticles were evaluated for zeta potential, particle size, entrapment efficiency, stability studies, and in vitro drug release studies. in vitro binding affinity of nanoparticles for hydroxyapatite was also measured. Bone morphology and its effect on bone mineral density were examined by using a glucocorticoid-induced osteoporosis rat model. RESULTS: The optimized nanoparticles were found to be amorphous and showed no drug-polymer interaction. The particle size of formulated nanoparticles varied from 196.8 ± 2.27nm to 524.8 ± 5.49 nm and the entrapment efficiency of nanoparticles varied from 41.9 ± 3.44% to 70.8 ± 4.46%, respectively. The nanoparticles showed sustained release behaviour (75% in 24 hr) of the drug followed by non-fickian drug release. The nanoparticles exhibited high binding affinity to bone cell receptors, increasing bone mineral density. A significant difference in calcium and phosphorous levels was observed in disease and treatment rats. Porous bone and significant improvement in porosity were observed in osteoporotic rats and treated rats, respectively (P < 0.05). CONCLUSION: Bone-targeting nanoparticles incorporating functionalized simvastatin can target bone. Thus, in order to distribute simvastatin subcutaneously for the treatment of osteoporosis, the developed nanoparticles may act as a promising approach.

Therapeutic potential of NOX inhibitors in neuropsychiatric disorders.

RATIONALE: Neuropsychiatric disorders encompass a broad category of medical conditions that include both neurology as well as psychiatry such as major depressive disorder, autism spectrum disorder, bipolar disorder, schizophrenia as well as psychosis. OBJECTIVE: NADPH-oxidase (NOX), which is the free radical generator, plays a substantial part in oxidative stress in neuropsychiatric disorders. It is thought that elevated oxidative stress as well as neuroinflammation plays a part in the emergence of neuropsychiatric disorders. Including two linked with membranes and four with subunits of cytosol, NOX is a complex of multiple subunits. NOX has been linked to a significant source of reactive oxygen species in the brain. NOX has been shown to control memory processing and neural signaling. However, excessive NOX production has been linked to cardiovascular disorders, CNS degeneration, and neurotoxicity. The increase in NOX leads to the progression of neuropsychiatric disorders. RESULT: Our review mainly emphasized the characteristics of NOX and its various mechanisms, the modulation of NOX in various neuropsychiatric disorders, and various studies supporting the fact that NOX might be the potential therapeutic target for neuropsychiatric disorders. CONCLUSION: Here, we summarizes various pharmacological studies involving NOX inhibitors in neuropsychiatric disorders.

Mechanistic correlation between mitochondrial permeability transition pores and mitochondrial ATP dependent potassium channels in ischemia reperfusion.

Mitochondrial dysfunction is one of the fundamental causes of ischemia reperfusion (I/R) damage. I/R refers to the paradoxical progression of cellular dysfunction and death that occurs when blood flow is restored to previously ischemic tissues. I/R causes a significant rise in mitochondrial permeability resulting in the opening of mitochondrial permeability transition pores (MPTP). The MPTP are broad, nonspecific channels present in the inner mitochondrial membrane (IMM), and are known to mediate the deadly permeability alterations that trigger mitochondrial driven cell death. Protection from reperfusion injury occurs when long-term ischemia is accompanied by short-term ischemic episodes or inhibition of MPTP from opening via mitochondrial ATP dependent potassium (mitoKATP) channels. These channels located in the IMM, play an essential role in ischemia preconditioning (PC) and protect against cell death by blocking MPTP opening. This review primarily focuses on the interaction between the MPTP and mitoKATP along with their role in the I/R injury. This article also describes the molecular composition of the MPTP and mitoKATP in order to promote future knowledge and treatment of diverse I/R injuries in various organs.

Mechanistic insights on impact of Adenosine monophosphate-activated protein kinase (AMPK) mediated signalling pathways on cerebral ischemic injury.

Cerebral ischemia is the primary cause of morbidity and mortality worldwide due to the perturbations in the blood supply to the brain. The brain triggers a cascade of complex metabolic and cellular defects in response to ischemic stress. However, due to the disease heterogeneity and complexity, ischemic injury's metabolic and cellular pathologies remain elusive, and the link between various pathological mechanisms is difficult to determine. Efforts to develop effective treatments for these disorders have yielded limited efficacy, with no proper cure available to date. Recent clinical and experimental research indicates that several neuronal diseases commonly coexist with metabolic dysfunction, which may aggravate neurological symptoms. As a result, it stands to a reason that metabolic hormones could be a potential therapeutic target for major NDDs. Moreover, fasting signals also influence the circadian clock, as AMPK phosphorylates and promotes the degradation of the photo-sensing receptor (cryptochrome). Here, the interplay of AMPK signaling between metabolic regulation and neuronal death and its role for pathogenesis and therapeutics has been studied. We have also highlighted a significant signaling pathway, i.e., the adenosine monophosphate-activated protein kinase (AMPK) involved in the relationship between the metabolism and ischemia, which could be used as a target for future studies therapeutics, and review some of the clinical progress in this area.

Pharmacological modulation of phosphodiesterase-7 as a novel strategy for neurodegenerative disorders.

Neurodegenerative illness develops as a result of genetic defects that cause changes at numerous levels, including genomic products and biological processes. It entails the degradation of cyclic nucleotides, cyclic adenosine monophosphate (cAMP), and cyclic guanosine monophosphate (cGMP). PDE7 modulates intracellular cAMP signalling, which is involved in numerous essential physiological and pathological processes. For the therapy of neurodegenerative illnesses, the normalization of cyclic nucleotide signalling through PDE inhibition remains intriguing. In this article, we shall examine the role of PDEs in neurodegenerative diseases. Alzheimer's disease, Multiple sclerosis, Huntington's disease, Parkinson's disease, Stroke, and Epilepsy are related to alterations in PDE7 expression in the brain. Earlier, animal models of neurological illnesses including Alzheimer's disease, Parkinson's disease, and multiple sclerosis have had significant results to PDE7 inhibitors, i.e., VP3.15; VP1.14. In addition, modulation of CAMP/CREB/GSK/PKA signalling pathways involving PDE7 in neurodegenerative diseases has been addressed. To understand the etiology, treatment options of these disorders mediated by PDE7 and its subtypes can be the focus of future research.

Adenosine as a Key Mediator of Neuronal Survival in Cerebral Ischemic Injury.

Several experimental studies have linked adenosine's neuroprotective role in cerebral ischemia. During ischemia, adenosine is formed due to intracellular ATP breakdown into ADP, further when phosphate is released from ADP, the adenosine monophosphate is formed. It acts via A1, A2, and A3 receptors found on neurons, blood vessels, glial cells, platelets, and leukocytes. It is related to various effector systems such as adenyl cyclase and membrane ion channels via G-proteins. Pharmacological manipulation of adenosine receptors by agonists (CCPA, ADAC, IB-MECA) increases ischemic brain damage in various in vivo and in vitro models of cerebral ischemia whereas, agonist can also be neuroprotective. Mainly, receptor antagonists (CGS15943, MRS1706) indicated neuroprotection. Later, various studies also revealed that the downregulation or upregulation of specific adenosine receptors is necessary during the recovery of cerebral ischemia by activating several downstream signaling pathways. In the current review, we elaborate on the dual roles of adenosine and its receptor subtypes A1, A2, and A3 and their involvement in the pathobiology of cerebral ischemic injury. Adenosine-based therapies have the potential to improve the outcomes of cerebral injury patients, thereby providing them with a more optimistic future.

Demethyleneberberine, a potential therapeutic agent in neurodegenerative disorders: a proposed mechanistic insight.

INTRODUCTION: Neurodegenerative disorders are a diverse variety of diseases that can be distinguished from developing degeneration of neurons in the CNS. Several alkaloids have shown mounting effects in neurodegenerative disorders, and berberine is one of them. Demethyleneberberine is a metabolite of berberine that has better blood-brain barrier crossing capacity. Demethyleneberberine possesses anti-inflammatory, anti-oxidant, and mitochondrial targeting properties. However, neither the pharmacological action nor the molecular mechanism of action of demethyleneberberine on neurodegenerative disorders has been explored yet. MATERIALS AND METHODS: A systematic literature review of PubMed, Medline, Bentham, Scopus, and EMBASE (Elseveier) databases was carried out with the help of keywords like "Demethyleneberberine; neuroinflammation; oxidative stress; Neuroprotective; Neurodegenerative disorders" till date. CONCLUSION: This review focus on the neuroprotective potential of demethyleneberberine in neurodegenerative disorders by attenuating different pathways, i.e., NF-κB, MAPK, and AMPK signalling.

Intervention of neuroinflammation in the traumatic brain injury trajectory: In vivo and clinical approaches.

TBI has been one of the top causes of death and morbidity worldwide, yet despite enormous efforts to discover neuroprotective therapeutics for this serious disease, no beneficial outcomes in human clinical trials have been reported to date. Traumatic brain injury (TBI) can occur as a result of any type of trauma, from a simple hit to the head to a penetrating injury to the brain. TBI causes delayed secondary damage events as a result of neurochemical, metabolic, and cellular alterations that account for many of the neurological impairments reported following TBI. We focus on the ability of soluble and cellular inflammatory mediators to promote repair and regeneration versus secondary injury and neurodegeneration in our discussion, which is structured around the kinetics of the immune response to TBI - from immediate triggers through chronic neuroinflammation. Neuroinflammation is caused by traumatic brain injury and can aggravate the progression of tissue deterioration. Immune cells respond acutely to signals from injured cells, develop neuroinflammation, and eventually cause pathology. So neuroinflammation and the immune system could be a target for TBI treatment. However, there are various approaches to the treatment of TBI. This review will provide the literature-based modulation of receptors, ion channels, transporters, and enzymes to attenuate traumatic brain injury.

Caspase-mediated regulation of the distinct signaling pathways and mechanisms in neuronal survival.

Caspases are intimately associated with altering various signaling pathways, resulting in programmed cell death or apoptosis. Apoptosis is necessary for the normal homeostasis of cells and their development. The untoward activation of apoptotic pathways indirectly or directly results in pathologies of various diseases. Identifying different caspases in apoptotic pathways directed the research to develop caspase inhibitors as therapeutic agents. However, no drug is available in the market that targets caspase inhibition and produces a therapeutic effect. Here, we will shed light on the role of caspases in the number of neuronal disorders and neurodegenerative diseases. The article reviews the findings about the activation of various upstream mechanisms associated with caspases in neurodegenerative disorders along with the recent progress in the generation of caspase inhibitors and the challenge faced in their development as therapeutic agents for neurological indications.

Poly (ADP-ribose) polymerase: An Overview of Mechanistic Approaches and Therapeutic Opportunities in the Management of Stroke.

Stroke is one of the leading causes of morbidity and mortality accompanied by blood supply loss to a particular brain area. Several mechanistic approaches such as inhibition of poly (ADP-ribose) polymerase, therapies against tissue thrombosis, and neutrophils lead to stroke's therapeutic intervention. Evidence obtained with the poly (ADP-ribose) polymerase (PARP) inhibition and animals having a deficiency of PARP enzymes; represented the role of PARP in cerebral stroke, ischemia/reperfusion, and neurotrauma. PARP is a nuclear enzyme superfamily with various isoforms, each with different structural domains and functions, and out of all, PARP-1 is the best-characterized member. It has been shown to perform multiple physiological as well as pathological processes, including its role in inflammation, oxidative stress, apoptosis, and mitochondrial dysfunction. The enzyme interacts with NF-κB, p53, and other transcriptional factors to regulate survival and cell death and modulates multiple downstream signaling pathways. Clinical trials have also been conducted using PARP inhibitors for numerous disorders and have shown positive results. However, additional information is yet to be established for the therapeutic intervention of PARP inhibitors in stroke. These agents' utilization appears to be challenging due to their unknown potential long-term side effects. PARP activity increased during ischemia, but its inhibition provided significant neuroprotection. Despite the increased interest in PARP as a pharmacological modulator for novel therapeutic therapies, the current review focused on stroke and poly ADP-ribosylation.

Pharmacological Postconditioning by Protocatechuic Acid Attenuates Brain Injury in Ischemia-Reperfusion (I/R) Mice Model: Implications of Nuclear Factor Erythroid-2-Related Factor Pathway.

Ischemia-reperfusion (I/R) injury often follows cardiovascular aberrations that predispose the patient to be neurological and cognitive abnormalities. Pharmacological postconditioning (pPoCo) aims to mitigate I/R origin cerebral infarction and neurobehavioral impairment. Protocatechuic acid (PCA) is a natural polyphenol possessing anti-oxidant and anti-inflammatory activities. This study investigated the effects of PCA pPoCo using a global I/R mice prototype. Mice were injected PCA (50 and 100 mg/kg) immediately after bilateral common carotid artery occlusion (17 min) followed by 24 h reperfusion. Trigonelline (10 mg/kg) was administered separately before I/R surgery to assess the role of the Nrf2 pathway in PCA and I/R treated mice. Results displayed neurological deficits 24 h post-reperfusion, and I/R triggered sensorimotor and memory deficits that were attenuated by PCA. PCA pPoCo increased antioxidants and Nrf2 expression in the brain against I/R injury. In I/R mice, PCA pPoCo attenuated lipid peroxidation, inflammatory cytokines (tumor necrosis factor-α, interleukin-1ß, interleukin-6), and myeloperoxidase activity. Histopathology revealed a decrease in total infarct area (TTC staining) and cortical neuron density by I/R surgery that was attenuated by PCA. Trigonelline antagonized beneficial effects of PCA pPoCo and attenuated Nrf2 pathway in I/R mice model. PCA pPoCo dose-dependently improves neurobehavioral functions against global I/R injury via the Nrf2 mechanism.

Pharmacological Modulation of Ubiquitin-Proteasome Pathways in Oncogenic Signaling.

The ubiquitin-proteasome pathway (UPP) is involved in regulating several biological functions, including cell cycle control, apoptosis, DNA damage response, and apoptosis. It is widely known for its role in degrading abnormal protein substrates and maintaining physiological body functions via ubiquitinating enzymes (E1, E2, E3) and the proteasome. Therefore, aberrant expression in these enzymes results in an altered biological process, including transduction signaling for cell death and survival, resulting in cancer. In this review, an overview of profuse enzymes involved as a pro-oncogenic or progressive growth factor in tumors with their downstream signaling pathways has been discussed. A systematic literature review of PubMed, Medline, Bentham, Scopus, and EMBASE (Elsevier) databases was carried out to understand the nature of the extensive work done on modulation of ubiquitin-proteasome pathways in oncogenic signaling. Various in vitro, in vivo studies demonstrating the involvement of ubiquitin-proteasome systems in varied types of cancers and the downstream signaling pathways involved are also discussed in the current review. Several inhibitors of E1, E2, E3, deubiquitinase enzymes and proteasome have been applied for treating cancer. Some of these drugs have exhibited successful outcomes in in vivo studies on different cancer types, so clinical trials are going on for these inhibitors. This review mainly focuses on certain ubiquitin-proteasome enzymes involved in developing cancers and certain enzymes that can be targeted to treat cancer.

Mechanistic insights and perspectives involved in neuroprotective action of quercetin.

Neurodegenerative diseases (NDDs) are the primary cause of disabilities in the elderly people. Growing evidence indicates that oxidative stress, mitochondrial dysfunction, neuroinflammation and apoptosis are associated with aging and the basis of most neurodegenerative disorders. Quercetin is a flavonoid with significant pharmacological effects and promising therapeutic potential. It is widely distributed among plants and typically found in daily diets mainly in fruits and vegetables. It shows a number of biological properties connected to its antioxidant activity. Neuroprotection by quercetin has been reported in many in vitro as well as in in vivo studies. However, the exact mechanism of action is still mystery and similarly there are a number of hypothesis exploring the mechanism of neuroprotection. Quercetin enhances neuronal longevity and neurogenesis by modulating and inhibiting wide number of pathways. This review assesses the food sources of quercetin, its pharmacokinetic profile, structure activity relationship and its pathophysiological role in various NDDs and it also provides a synopsis of the literature exploring the relationship between quercetin and various downstream signalling pathways modulated by quercetin for neuroprotection for eg. nuclear factor erythroid 2-related factor 2 (Nrf2), Paraoxonase-2 (PON2), c-Jun N-terminal kinase (JNK), Tumour Necrosis Factor alpha (TNF-α), Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (PGC-1α), Sirtuins, Mitogen-activated protein kinases (MAPKs) signalling cascades, CREB (Cyclic AMP response element binding protein) and Phosphoinositide 3- kinase(PI3K/Akt). Therefore, the aim of the present review was to elaborate on the cellular and molecular mechanisms of the quercetin involved in the protection against NDDs.

Therapeutic modulation of the phosphatidylinositol 3-kinases (PI3K) pathway in cerebral ischemic injury.

The cerebral ischemic reperfusion injury may leads to morbidity and mortality in patients. phosphatidylinositol 3-kinase (PI3K) signaling pathway has been believed to work in association with its downstream targets, other receptors, and pathways that may offer antioxidant, anti-inflammatory, anti-apoptotic effects, neuroprotective role in neuronal excitotoxicity. This review elaborates the mechanistic interventions of the PI3K pathway in cerebral ischemic injury in context to nuclear factor erythroid 2-related factor 2 (Nrf2) regulation, Hypoxia-inducible factor 1 signaling (HIF-1), growth factors, Endothelial NOS (eNOS) proinflammatory cytokines, Erythropoietin (EPO), Phosphatase and tensin homologous protein of chromosome 10 gene (PTEN) signaling, NF-κB/Notch signaling, c-Jun N-terminal kinase (JNK) and Glycogen synthase kinase-3ß (GSK-3ß) signaling pathway. Evidences showing the activation of PI3K inhibits apoptotic pathway, which results in its neuroprotective effect in ischemic injury. Despite discussing the therapeutic role of the PI3K pathway in treating cerebral ischemic injury, the review also enlighten the selective modulation of PI3K pathway with activators and inhibitors which may provide promising results in clinical and preclinical settings.

Therapies modulating insulin resistance in Parkinson's disease: A cross talk.

Parkinson's disease (PD) is a neurodegenerative disorder linked with aging and primarily involves dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc). The deregulation of genes associated with T2D has been demonstrated by proteomic research on Parkinson's symptoms patients. Various common pathways likely to link neurodegenerative mechanisms of PD include abnormal mitochondrial function, inflammation, apoptosis/autophagy and insulin signalling/glucose metabolism in T2DM. Several pathway components including phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt), glycogen synthase kinase-3 beta (GSK-3ß) and nuclear factor kappa B (NF-κB) impairment is observed in PD. Numerous novel targets are being pursued in preclinical and clinical trials that target metabolic dysfunction in PD; that elevate insulin signaling pathways in dopaminergic neurons, and show improvement in motor and cognitive measures and produce significant neuroprotective effects in PD patients.