Parkinson's disease (PD) is a degenerative central nervous system disease pathologically attributed to dopaminergic neuron damage in the substantia nigra. Noscapine is a natural alkaloid with several benefits, including anti-inflammatory, neural protection, and anti-oxidant effects. Hence, the current study evaluated the protective effects of Noscapine against paraquat (PQ)-induced Parkinson's disease model in rats. Male Wistar rats were into six groups: sham and PQ-induced models treated with vehicle, vitamin-E (20 mg/kg/d), or Noscapine (6, 18, and 55 mg/kg/d) for four weeks. Meanwhile, the rats were assessed for weight and food consumption (FC) daily and PD-associated behavior changes using rotarod, bar, and parallel bar tests every week. The animals were ethically sacrificed at the end of the study, and biochemical, immunological, and histopathological markers were measured in the brain. As a result, the levels of weight, FC, parallel bar, and rotarod test (both speed and latency), number of neurons, total thiol content, and interleukin-10 (IL-10) were significantly reduced. In contrast, the levels of dark neurons, TNF-α, bar test, and malondialdehyde (MDA) were markedly increased in the PQ-vehicle group compared to the sham group (P < 0.001-0.5). In contrast, comedication with Noscapine significantly reversed the histological damages and improved deteriorated behavioral, biochemical, and immunological parameters in a dose-dependent manner compared to the PQ-vehicle group (0.001-0.05). Taken together, it was determined that using Noscapine has antiparkinsonian effects and improved behavioral tests, catalepsy, bradykinesia, and motor dysfunction and has a protective impact on the brain's neurons through its anti-oxidant and anti-inflammatory properties.

Sulfonylureas (SUs)-a class of drugs primarily used to treat type 2 diabetes-have recently attracted interest for their potential anticancer properties. While some studies have explored the chemical modification or design of new SU derivatives, our work instead centers on biological evaluations of all commercially available SUs in combination with doxorubicin (DOXO). These antidiabetic agents act by stimulating insulin secretion via KATP channel inhibition, and because KATP channels share structural features with ATP-binding cassette (ABC) transporters involved in multidrug resistance (e.g., P-glycoprotein, MRP1, and MRP2), SUs may also reduce cancer cell drug efflux. In this study, we systematically examined each commercially available SU for potential synergy with DOXO in a panel of human cancer cell lines. Notably, combining DOXO with glimepiride (GLIM), the newest SU, results in a 4.4-fold increase in cytotoxicity against MCF-7 breast cancer cells relative to DOXO alone. Mechanistic studies suggest that the observed synergy may arise from increased intracellular accumulation of DOXO. Preliminary in vivo experiments support these findings, showing that DOXO (5 mg/kg, i.v.) plus GLIM (4 mg/kg, i.p.) is more effective at inhibiting 4T1 tumor growth in mice than DOXO alone. Additionally, we show that adding a small amount of the surfactant Tween-80 to culture media affects SU binding to bovine serum albumin (BSA), potentially unmasking anticancer effects of SUs that strongly bind to proteins. Overall, these results underscore the potential of repurposing existing SUs to enhance standard chemotherapy regimens.

Glucose metabolism is essential for the maintenance and function of the central nervous system. Although the brain constitutes only 2% of the body weight, it consumes approximately 20% of the body's total energy, predominantly derived from glucose. This high energy demand of the brain underscores its reliance on glucose to fuel various functions, including neuronal activity, synaptic transmission, and the maintenance of ion gradients necessary for nerve impulse transmission. Increasing evidence shows that many neurodegenerative diseases, including Parkinson's disease (PD), are associated with abnormalities in glucose metabolism. PD is characterized by the progressive loss of dopaminergic neurons in the substantia nigra, accompanied by the accumulation of α-synuclein protein aggregates. These pathological features are exacerbated by mitochondrial dysfunction, oxidative stress, and neuroinflammation, all of which are influenced by glucose metabolism disruptions. Emerging evidence suggests that targeting glucose metabolism could offer therapeutic benefits for PD. Several antidiabetic drugs have shown promise in animal models and clinical trials for mitigating the symptoms and progression of PD. This review explores the current understanding of the association between PD and glucose metabolism, emphasizing the potential of antidiabetic medications as a novel therapeutic approach. By improving glucose uptake and utilization, enhancing mitochondrial function, and reducing neuroinflammation, these drugs could address key pathophysiological mechanisms in PD, offering hope for more effective management of this debilitating disease.

Background and Objectives: Parkinson's disease (PD) is a pathological state characterized by a combined set of abnormal movements including slow motion, resting tremors, profound stiffness of skeletal muscles, or obvious abnormalities in posture and gait, together with significant behavioral changes. Until now, no single therapeutic modality was able to provide a complete cure for PD. This work was a trial to assess the immunomodulatory effects of canagliflozin with or without levodopa/carbidopa on rotenone-induced parkinsonism in Balb/c mice. Materials and Methods: In a mouse model of PD, the effect of canagliflozin with or without levodopa/carbidopa was assessed at the behavioral, biochemical, and histopathological levels. Results: The combination of levodopa/carbidopa and canagliflozin significantly mitigated the changes induced by rotenone administration regarding the behavioral tests, striatal dopamine, antioxidant status, Nrf2 content, SIRT-1/PPAR-gamma axis, RAGE/HMGB1/NF-κB signaling, and mitochondrial dysfunction; abrogated the neuroinflammatory responses, and alleviated the histomorphologic changes induced by rotenone administration relative to the groups that received either levodopa/carbidopa or canagliflozin alone. Conclusions: Canagliflozin may represent a new adjuvant therapeutic agent that may add value to the combatting effects of levodopa/carbidopa against the pathological effects of PD.

As a dietary strategy, methionine restriction has been reported to promote longevity and regulate metabolic disorders. However, the role and possible regulatory mechanisms underlying methionine in neurodegenerative diseases such as Alzheimer's disease (AD), remain unexplored. This study utilized the data from BXD recombinant inbred (RI) mice to establish a correlation between the AD phenotype in mice and methionine level. Gene enrichment analysis indicated that the genes associated with the concentration of methionine in the midbrain are involved in the dopaminergic synaptic signaling pathway. Protein interaction network analysis revealed that glycogen synthase kinase 3 beta (GSK-3β) was a key regulator of the dopaminergic synaptic pathway and its expression level was significantly correlated with the AD phenotype. Finally, in vitro experiments demonstrated that methionine deprivation could reduce the expression of Aβ and phosphorylated Tau, suggesting that lowering methionine levels in humans may be a preventive or therapeutic strategy for AD. In conclusion, our findings support that methionine is a high risk factor for AD. These findings predict potential regulatory network, theoretically supporting methionine restriction to prevent AD.

Type 2 diabetes (T2D) and Parkinson's disease (PD) are chronic disorders that have a significant health impact on a global scale. Epidemiological, preclinical, and clinical research underpins the assumption that insulin resistance and chronic inflammation contribute to the overlapping aetiologies of T2D and PD. This narrative review summarises the recent evidence on the contribution of T2D to the initiation and progression of PD brain pathology. It also briefly discusses the rationale and potential of alternative pharmacological interventions for PD treatment.

Paraquat (1,1'-dimethyl-4-4'-bipyridinium dichloride) exposure is well-established as a neurotoxic agent capable of causing neurological deficits in offspring. This study aimed to investigate therapeutic effects of Arbutus unedo L. aqueous extract (AU) against paraquat (PQ) exposure.

For that the phytoconstituents of AU was determined by LC/MS, and then its antioxidant potential was assessed by DPPH and ABTS assays. The assessment included its impact on cell viability and mitochondrial metabolism using N27 dopaminergic cells. Additionally, we evaluated the effects of prenatal PQ exposure on motor coordination, dopamine levels, trace element levels, and total antioxidant capacity (TAC) in rat progeny.

The phytochemical profile of AU extract revealed the presence of 35 compounds, primarily phenolic and organic acids, and flavonoids. This accounted for its strong in vitro antioxidant activities against DPPH and ABTS radicals, surpassing the activities of vitamin C. Our findings demonstrated that AU effectively inhibited PQ-induced loss of N27 rat dopaminergic neural cells and significantly enhanced their mitochondrial respiration. Furthermore, daily post-treatment with AU during the 21 days of the rat's pregnancy alleviated PQ-induced motor deficits and akinesia in rat progeny. These effects inhibited dopamine depletion and reduced iron levels in the striatal tissues. The observed outcomes appeared to be mediated by the robust antioxidant activity of AU, effectively counteracting the PQ-induced decrease in TAC in the blood plasma of rat progeny. These effects could be attributed to the bioactive compounds present in AU, including phenolic acids such as gallic acid and flavonoids such as quercetin, rutin, apigenin, glucuronide, and kaempferol, all known for their potent antioxidant capacity.

In conclusion, this preclinical study provided the first evidence of the therapeutic potential of AU extract against PQ-induced neurotoxicity. These findings emphasize the need for further exploration of the clinical applicability of AU in mitigating neurotoxin-induced brain damage.

Parkinson's disease (PD) is a neuromuscular ailment that affects people in their later years and causes both motor and non-motor deficits. Receptor-interacting protein-1 (RIP-1) is a critical participant in necroptotic cell death, possibly through an oxidant-antioxidant imbalance and cytokine cascade activation in PD pathogenesis. The present study examined the role of RIP-1-mediated necroptosis and neuroinflammation in the MPTP-induced PD mouse model, as well as their protection by Necrostatin-1s (an RIP signalling inhibitor), antioxidant DHA and their functional interaction. BALB/c mice were given acute MPTP therapy (4 injections of 15 mg/kg i.p. at 2-h intervals) on day 1. After MPTP intoxication, Necrostatin-1s (Nec-1s; 8 mg/kg/day, i.p.) and DHA (300 mg/kg/day, p.o.) treatments were given once daily for 7 days. The Nec-1s treatment prevented MPTP-induced behavioural, biochemical and neurochemical alterations, and the addition of DHA increases Nec-1s' neuroprotective impact. In addition, Nec-1s and DHA significantly improve the survival of TH-positive dopaminergic neurons and lower expression levels of the inflammatory cytokines, IL-1β and TNF-α. Furthermore, Nec-1s dramatically reduced RIP-1 expression, whereas DHA had little effect. Our research raises the possibility that neuroinflammatory signalling and acute MPTP-induced necroptosis are both mediated by TNFR1-driven RIP-1 activity. In this study, RIP-1 ablation through Nec-1s and the addition of DHA showed a reduction in the levels of pro-inflammatory and oxidative markers, as well as protection from MPTP-driven dopaminergic degeneration and neurobehavioural changes, suggesting potential therapeutic applications. For a better understanding, additional research about the mechanism(s) behind Nec-1s and DHA is required.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by both motor and non-motor features. The current treatment regimen for PD are dopamine enhancers which have been reported to worsen the disease prognosis after long term treatment, thus, the need for better treatment options. This study sought to investigate the protective action of Double Stem Cell® (DSC), a blend of stem cells extracts from Swiss apples (Malus Domestica) and Burgundy grapes (Vitis vinifera) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism in mice and genetic model of PD in Drosophila melanogaster. Male albino mice were pretreated with MPTP (4 × 20 mg/kg, i.p., two hourly in 8 h), twelve hours before administration of DSC (8, 40, or 200 mg/kg, p.o.). Thereafter, behavioural, biochemical and immunohistochemical assays were carried out. The impact of vehicle or DSC supplementation on α-synuclein aggregation was evaluated in Drosophila melanogaster using the UAS-Gal4 system, female DDC-Gal4 flies were crossed with male UAS-α-synuclein, the progenies were examined for fecundity, locomotion, memory, and lifespan. MPTP-induced motor deficits in open field test (OFT), working memory impairment (Y-maze test (YMT)) and muscle incoordination (rotarod test) were ameliorated by DSC (8, 40 or 200 mg/kg) through dose-dependent and significant improvements in motor, cognitive and motor coordination. Moreso, MPTP exposure caused significant increase in lipid peroxidation and decrease in antioxidant enzymes activities (glutathione, catalase and superoxide dismutase) in the midbrain which were attenuated by DSC. MPTP-induced expression of microglia (iba-1), astrocytes (glia fibrillary acidic protein; GFAP) as well as degeneration of dopamine neurons (tyrosine hydroxylase positive neurons) in the substantia nigra (SN) were reversed by DSC. Supplementation of flies feed with graded concentration of DSC (0.8, 4 or 20 mg/ml) did not affect fecundity but improved climbing activity and lifespan. Findings from this study showed that Double Stem Cell improved motor and cognitive functions in both mice and Drosophila through attenuation of neurotoxin-induced oxidative stress and neuroinflammation.

It is well established that there is a link between type 2 diabetes mellitus and Parkinson's disease (PD) evidenced in faster progression and more severe phenotype in patients living with diabetes suggestive of shared cellular pathways; hence, antidiabetic drugs could be a possible treatment options for disease modification. This study evaluated the effect of glimepiride (GMP), a third generation sulphonylurea, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in mice. Sixty mice were divided randomly into six individual groups of 10 mice each and dose orally as follows: group 1: vehicle (10 ml/kg, p.o.); group 2: MPTP (20 mg/kg, i.p. × 4 at 2-h interval); groups 3-5: GMP (1, 2, or 4 mg/kg, p.o.) + MPTP (20 mg/kg, i.p. × 4 at 2-h interval); and group 6: GMP (4 mg/kg, p.o.). Effect of glimepiride on motor activities were appraised with the use of open-field test and rotarod performance while non-motor activity was evaluated using force swim test (FST; depression) and Y-maze test (working memory). MPTP induced significant decrease in latency to fall on rotarod, distance covered/rearing in open field, mean speed and climbing in FST, and percentage alternation behavior in Y-maze suggestive of motor and non-motor dysfunction. However, MPTP-induced motor and non-motor dysfunction were ameliorated with glimepiride post-treatment. In addition, MPTP-induced increase in oxidative stress parameters and cholinergic neurotransmission was attenuated by glimepiride. In addition, MPTP-induced nigral dopamine neuron loss (decrease in tyrosine hydroxylase-positive neuron (TH)) and neuroinflammation (activation of glial fibrillary acid protein (GFAP) and ionized calcium binding adaptor molecule 1 (iba-1)) were ameliorated by GMP administration. This study showed that glimepiride ameliorates MPTP-induced PD motor and non-motor deficits through enhancement of antioxidant defense signaling and attenuation of neuroinflammatory markers. Thus, this could be useful as a disease-modifying therapy in the management of PD.

Tauopathy is a group of neurodegenerative diseases in which the pathogenesis processes are related to tau protein. The imbalances between the activities of kinases and phosphatases of tau protein lead to tau hyperphosphorylation and subsequent neurodegeneration. Numerous studies suggest a strong linkage between type 2 diabetes mellitus (T2D) and neurodegenerative diseases. Therefore, finding a drug with a dual therapeutic activity against T2D and neuroprotective will be a promising idea. Hence, the potential neuroprotective effect of Glimepiride (GPD) against tauopathy was evaluated in the current study.

P301S mice model was employed for tauopathy and C57BL/6 wild type mice (WT) was used as control. Phosphorylated and acetylated tau protein levels was assessed in cortex and hippocampus by western blot. Effect of GPD on tauopathy related enzymes, neuroinflammation, apoptotic markers were evaluated. Furthermore, the neuroprotective effects against anxiety like behavior and motor impairment was analyzed using Parallel rod floor and Open field tests.

GPD significantly ameliorates motor impairment, anxiety like behavior and neurodegeneration in P301S mice. Phosphorylated tau and acetylated tau were significantly decreased in both cortex and hippocampus of P301S mice via decreasing GSK3β, increasing ratio of phosphorylated-AKT to total-AKT, increasing PP2A and normalization of CDK5 levels. Furthermore, GPD treatment also decreased neuroinflammation and apoptosis by reducing NF-kB, TNF-α and caspase 3 levels.

The current data suggests that GPD exerts a protective effect against tauopathy, behavioural consequences, neurodegeneration, neuroinflammation and apoptosis. GPD is therefore a promising agent for the treatment of neurodegenerative diseases associated with tauopathy.

Parkinson's disease (PD) is a neurodegenerative disorder that gradually develops over time in a progressive manner. The main culprit behind the disease pathology is dopaminergic deficiency in Substantia nigra Pars Compacta (SNpc) due to neuronal degeneration. However, there are other factors that are not only associated with it but also somehow responsible for inception of pathology. Metabolic syndrome is one such risk factor for PD. Metabolic syndrome is a cluster of diseases mainly including diabetes, hypertension, obesity, and hyperlipidemia which pose a risk for developing cardiovascular disorders. All of these disorders have their own pathological pathways that intertwine with PD pathology. This leads to alpha-synuclein aggregation, neuroinflammation, mitochondrial dysfunction, and oxidative stress which are facets in initiating PD pathology. Although few reports are available, this area is underexplored and has contradictory views. Hence, further studies are needed in order to establish a definite relationship between PD and metabolic syndrome. In this review, we aim to elucidate the molecular mechanisms to confirm the association between them and pave the way for potential repurposing of therapies.

Parkinson disease (PD) is a neurodegenerative disorder of the motor activity of the brain, regulated by dopaminergic neurons of substantia nigra, resulting in an increased density of histaminergic fibers. This study was aimed to evaluate the effects of H1 antagonist's ebastine and levocetirizine in PD per se and in combination. Animals were divided into 9 groups (n = 10). Group 1 received carboxymethyl cellulose CMC (1 mL/kg). Group II was treated with haloperidol (1 mg/kg) (diseased group). Group III was treated with levodopa/carbidopa (levo 20 mg/kg). Groups IV and V were treated with ebastine at dose levels of 2 and 4 mg/kg, respectively. Groups VI and VII were treated with levocetirizine at dose levels of 0.5 and 1 mg/kg, respectively. Group VIII was treated with ebastine (4 mg/kg) + levo (20 mg/kg) in combination. Group IX was treated with levocetirizine (1 mg/kg) + levo (20 mg/kg). PD was induced with haloperidol (1 mg/kg iv, once daily for 23 days) for a duration of 30 min. Behavioral tests like rotarod, block and triple horizontal bars, actophotometer, and open field were performed. Biochemical markers of oxidative stress, i.e., SOD, CAT, GSH, MDA, dopamine, serotonin, and nor-adrenaline and nitrite, were determined. Histamine, mRNA expression of α-synuclein, and TNF-α level in the serum and brain of mice were analyzed. Endogenous biochemical markers were increased except mRNA expression of α-synuclein, which was reduced. In combination therapy with the standard drug, ebastine (4 mg/kg) significantly improved the cataleptic state and dopamine levels, but no significant difference in the renal and liver functioning tests was observed. This study concluded that ebastine (4 mg/kg) might work in the treatment of PD as it improves the cataleptic state in haloperidol-induced catalepsy.

The relationship between diabetes mellitus and Parkinson's disease has been described in several epidemiological studies over the 1960s to date. Molecular studies have shown the possible functional link between insulin and dopamine, as there is strong evidence demonstrating the action of dopamine in pancreatic islets, as well as the insulin effects on feeding and cognition through central nervous system mechanism, largely independent of glucose utilization. Therapies used for the treatment of type 2 diabetes mellitus appear to be promising candidates for symptomatic and/or disease-modifying action in neurodegenerative diseases including Parkinson's disease, while an old dopamine agonist, bromocriptine, has been repositioned for the type 2 diabetes mellitus treatment. This review will aim at reappraising the different studies that have highlighted the dangerous liaisons between diabetes mellitus and Parkinson's disease.

Big data approaches have profoundly influenced state-of-the-art in many fields of research, with toxicology being no exception. Here, we use Parkinson's disease as a window through which to explore the challenges of a dual explosion of metabolomic data addressing the myriad environmental exposures individuals experience and genetic analyses implicating many different loci as risk factors for disease. We argue that new experimental approaches are needed to convert the growing body of omics data into molecular mechanisms of disease that can be therapeutically targeted in specific patients. We outline one attractive strategy, which capitalizes on the rapid generation time and advanced molecular tools available in the fruit fly, Drosophila, to provide a platform for mechanistic dissection and drug discovery.

Prenatal exposure to valproic acid (VPA) has been shown to increase the risk of autism in children. This study examined the effect of metformin on VPA-induced autism spectrum disorders in rats. Pregnant albino rats administered VPA (500 mg/kg, i.p.) or normal saline (10 mL/kg, i.p.; vehicle-control) on gestational day 12.5. The pups were given metformin (5, 50 or 500 mg/kg, p.o.) or vehicle (10 mL/kg, p.o.) daily from postnatal day (PND) 21-50. Social behaviour, spatial learning/reference memory, repetitive behaviour and anxiety were assessed using the three-chamber social assay, Morris water maze (MWM), Y maze and elevated plus maze tests (EPM), respectively. On PND 51, the animals were euthanized and brains removed for biochemical assay. In utero VPA exposure caused significant reduction in sociability index, social novelty preference index in three-chambered apparatus and spatial learning and reference memory deficits in the MWM task as well as increase in repetitive/anxiety-like behaviour in Y maze and EPM tests, respectively, which were ameliorated by post-treatment with metformin in a dose-dependent manner. Moreover, prenatal VPA increased malondialdehyde (MDA) and nitrite levels as well as deficits in antioxidant enzymes activities in the hippocampus and prefrontal cortex (PFC) which were attenuated by metformin administration. Similarly, VPA-induced increase in acetylcholinesterase activity in the hippocampus and PFC were attenuated by postnatal treatment with metformin. Findings from this study showed that postnatal administration of metformin prevented valproic acid-induced autistic-like behaviour. Hence, metformin could be a potential adjunct in the management of autism spectrum disorders.

The detrimental effects of constant hyperglycemia on neural function have been quantitatively and qualitatively evaluated in the setting of diabetes mellitus. Some of the hallmark features of diabetic encephalopathy (DE) are impaired synaptic adaptation and diminished spatial learning capacity. Chronic and progressive cognitive dysfunction, perpetuated by several positive feedback mechanisms in diabetic subjects, facilitates the development of early-onset dementia and Alzheimer's disease. Despite the numerous clinical manifestations of DE having been described in detail and their pathophysiological substrate having been elucidated in both type 1 and type 2 diabetes mellitus, an effective therapeutic approach is yet to be proposed. Therefore, the aim of this review is to summarize the growing body of evidence concerning the effect of current antidiabetic treatment options on diabetic and non-DE.