The Influence of Kynurenine Metabolites on Neurodegenerative Pathologies.

As the kynurenine pathway's links to inflammation, the immune system, and neurological disorders became more apparent, it attracted more and more attention. It is the main pathway through which the liver breaks down Tryptophan and the initial step in the creation of nicotinamide adenine dinucleotide (NAD+) in mammals. Immune system activation and the buildup of potentially neurotoxic substances can result from the dysregulation or overactivation of this pathway. Therefore, it is not shocking that kynurenines have been linked to neurological conditions (Depression, Parkinson's, Alzheimer's, Huntington's Disease, Schizophrenia, and cognitive deficits) in relation to inflammation. Nevertheless, preclinical research has demonstrated that kynurenines are essential components of the behavioral analogs of depression and schizophrenia-like cognitive deficits in addition to mediators associated with neurological pathologies due to their neuromodulatory qualities. Neurodegenerative diseases have been extensively associated with neuroactive metabolites of the kynurenine pathway (KP) of tryptophan breakdown. In addition to being a necessary amino acid for protein synthesis, Tryptophan is also transformed into the important neurotransmitters tryptamine and serotonin in higher eukaryotes. In this article, a summary of the KP, its function in neurodegeneration, and the approaches being used currently to target the route therapeutically are discussed.

Oxidative stress and COVID-19-associated neuronal dysfunction: mechanisms and therapeutic implications.

Severe acute respiratory syndrome (SARS)-CoV-2 virus causes novel coronavirus disease 2019 (COVID-19), and there is a possible role for oxidative stress in the pathophysiology of neurological diseases associated with COVID-19. Excessive oxidative stress could be responsible for the thrombosis and other neuronal dysfunctions observed in COVID-19. This review discusses the role of oxidative stress associated with SARS-CoV-2 and the mechanisms involved. Furthermore, the various therapeutics implicated in treating COVID-19 and the oxidative stress that contributes to the etiology and pathogenesis of COVID-19-induced neuronal dysfunction are discussed. Further mechanistic and clinical research to combat COVID-19 is warranted to understand the exact mechanisms, and its true clinical effects need to be investigated to minimize neurological complications from COVID-19.

Role of cGAS-Sting Signaling in Alzheimer's Disease.

There is mounting evidence that the development of Alzheimer's disease (AD) interacts extensively with immunological processes in the brain and extends beyond the neuronal compartment. Accumulation of misfolded proteins can activate an innate immune response that releases inflammatory mediators and increases the severity and course of the disease. It is widely known that type-I interferon-driven neuroinflammation in the central nervous system (CNS) accelerates the development of numerous acute and chronic CNS diseases. It is becoming better understood how the cyclic GMP-AMP synthase (cGAS) and its adaptor protein Stimulator of Interferon Genes (STING) triggers type-I IFN-mediated neuroinflammation. We discuss the principal elements of the cGAS-STING signaling pathway and the mechanisms underlying the association between cGAS-STING activity and various AD pathologies. The current understanding of beneficial and harmful cGAS-STING activity in AD and the current treatment pathways being explored will be discussed in this review. The cGAS-STING regulation offers a novel therapeutic opportunity to modulate inflammation in the CNS because it is an upstream regulator of type-I IFNs.

Health influence of SARS-CoV-2 (COVID-19) on cancer: a review.

The novel coronavirus, namely, SARS-CoV-2 (COVID-19), broke out two years ago and has caused major global health issues. Adequate treatment options are still lacking for the management of COVID-19 viral infections. Many patients afflicted with COVID-19 may range from asymptomatic to severe symptomatic, triggering poor clinical outcomes, morbidity, and mortality. Cancer is one of the leading causes of death worldwide. It is pertinent to re-examine cancer prevalence during the COVID-19 pandemic to prevent mortality and complications. Understanding the impact of SARS-CoV-2 on cancer is key to appropriate healthcare measures for the treatment and prevention of this vulnerable population. Data was acquired from PubMed using key search terms. Additional databases were utilized, such as the Centers for Disease Prevention and Control, American Cancer Society (ACS), and National Cancer Institute (NCI). Cancer patients are more prone to SARS-CoV-2 infection and exhibit poor health outcomes, possibly due to a chronic immunosuppressive state and anticancer therapies. Male sex, older age, and active cancer disease or previous cancer are risk factors for COVID-19 infection, leading to possible severe complications, including morbidity or mortality. The speculated mechanism for potentially higher mortality or COVID-19 complications is through reduced immune system function and inflammatory processes through cancer disease, anticancer therapy, and active COVID-19 infection. This review includes prostate, breast, ovarian, hematologic, lung, colorectal, esophageal, bladder, pancreatic, cervical, and head and neck cancers. This review should help better maintain the health of cancer patients and direct clinicians for COVID-19 prevention to improve the overall health outcomes.

ß-hydroxybutyric acid attenuates oxidative stress and improves markers of mitochondrial function in the HT-22 hippocampal cell line.

Ketone bodies have been the topic of research for their possible therapeutic neurotropic effects in various neurological diseases such as Parkinson's disease, dementia, and seizures. However, continuing research on ketone bodies as a prophylactic agent for decreasing the risk for various neurodegenerative diseases is currently required. In this paper, hippocampal HT-22 cells were treated with ß-hydroxybutyric acid at different doses to elucidate the neurotropic effects. In addition, markers of oxidative stress, mitochondrial function, and apoptosis were investigated. As a result, the ketone body (ß-hydroxybutyric acid) showed a significant increase in hippocampal neuronal viability at a moderate dose. Results show that ß-hydroxybutyric acid exhibited antioxidant effect by decreasing prooxidant oxidative stress markers such as reactive oxygen species, nitrite content, and increasing glutathione content leading to decreased lipid peroxidation. Results show that ß-hydroxybutyric acid improved mitochondrial functions by increasing Complex-I and Complex-IV activities and showing that ß-hydroxybutyric acid significantly reduces caspase-1 and caspase-3 activities. Finally, using computational pharmacokinetics and molecular modeling software, we validated the pharmacokinetic effects and pharmacodynamic (N-Methyl-D-aspartic acid and acetylcholinesterase) interactions of ß-hydroxybutyric acid. The computational studies demonstrate that ß-hydroxybutyric acid can interact with N-Methyl-D-aspartic acid receptor and cholinesterase enzyme (the prime pharmacodynamic targets for cognitive impairment) and further validates its oral absorption, distribution into the central nervous system. Therefore, this work highlights the neuroprotective potential of ketone bodies in cognitive-related neurodegenerative diseases.

Predictable hematological markers associated with cognitive decline in valid rodent models of cognitive impairment.

Endogenous (hyperglycemia) and exogenous (therapeutic, prophylactic, street drugs) factors can considerably contribute to cognitive impairment (CI). Currently, there are few invasive and/or noninvasive markers that correlate with CI and those that do exist require expensive or invasive techniques to predict and accurately measure the cognitive decline. Therefore, we sought to determine hematological markers as predictors of CI in two different chemically induced valid rodent models of CI (streptozotocin induced hyperglycemic model and chemotherapy [doxorubicin/cyclophosphamide] treated rodent model). Hematological markers were analyzed in the above rodent models of CI CI and compared to their respective control groups. There was a significant increase in creatinine kinase, lactate dehydrogenase and aspartate aminotransferase (AST) in the chemotherapy group. Blood urea nitrogen (BUN), alkaline phosphatase (ALP), bilirubin, creatinine and glucose levels were significantly increased in the streptozotocin group. Interestingly, triglycerides were significantly elevated in both the streptozotocin and chemotherapy groups. Previous studies with human subjects have shown a potential link between the increase in triglyceride levels and CI. Likewise, our data indicate a notable correlation with an increase in triglycerides to cognitive impairment in the rodent models. This suggests elevated levels of triglycerides could prove to be a potential noninvasive hematological marker for the increased risk of CI. Further studies are warranted to determine the causal relationship between elevated triglyceride levels and CI.

Role of Adiponectin in Central Nervous System Disorders.

Adiponectin, the most abundant plasma adipokine, plays an important role in the regulation of glucose and lipid metabolism. Adiponectin also possesses insulin-sensitizing, anti-inflammatory, angiogenic, and vasodilatory properties which may influence central nervous system (CNS) disorders. Although initially not thought to cross the blood-brain barrier, adiponectin enters the brain through peripheral circulation. In the brain, adiponectin signaling through its receptors, AdipoR1 and AdipoR2, directly influences important brain functions such as energy homeostasis, hippocampal neurogenesis, and synaptic plasticity. Overall, based on its central and peripheral actions, recent evidence indicates that adiponectin has neuroprotective, antiatherogenic, and antidepressant effects. However, these findings are not without controversy as human observational studies report differing correlations between plasma adiponectin levels and incidence of CNS disorders. Despite these controversies, adiponectin is gaining attention as a potential therapeutic target for diverse CNS disorders, such as stroke, Alzheimer's disease, anxiety, and depression. Evidence regarding the emerging role for adiponectin in these disorders is discussed in the current review.

Autotaxin⁻Lysophosphatidic Acid Signaling in Alzheimer's Disease.

The brain contains various forms of lipids that are important for maintaining its structural integrity and regulating various signaling cascades. Autotaxin (ATX) is an ecto-nucleotide pyrophosphatase/phosphodiesterase-2 enzyme that hydrolyzes extracellular lysophospholipids into the lipid mediator lysophosphatidic acid (LPA). LPA is a major bioactive lipid which acts through G protein-coupled receptors (GPCRs) and plays an important role in mediating cellular signaling processes. The majority of synthesized LPA is derived from membrane phospholipids through the action of the secreted enzyme ATX. Both ATX and LPA are highly expressed in the central nervous system. Dysfunctional expression and activity of ATX with associated changes in LPA signaling have recently been implicated in the pathogenesis of Alzheimer's disease (AD). This review focuses on the current understanding of LPA signaling, with emphasis on the importance of the autotaxin⁻lysophosphatidic acid (ATX⁻LPA) pathway and its alterations in AD and a brief note on future therapeutic applications based on ATX⁻LPA signaling.

Comparing the dopaminergic neurotoxic effects of benzylpiperazine and benzoylpiperazine.

Benzylpiperazine has been designated as Schedule I substance under the Controlled Substances Act by Drug Enforcement Administration. Benzylpiperazine is a piperazine derivative, elevates both dopamine and serotonin extracellular levels producing stimulatory and hallucinogenic effects, respectively, similar to methylenedioxymethamphetamine (MDMA). However, the comparative neurotoxic effects of Piperazine derivatives (benzylpiperazine and benzoylpiperazine) have not been elucidated. Here, piperazine derivatives (benzylpiperazine and benzoylpiperazine) were synthesized in our lab and the mechanisms of cellular-based neurotoxicity were elucidated in a dopaminergic human neuroblastoma cell line (SH-SY5Y). We evaluated the in vitro effects of benzylpiperazine and benzoylpiperazine on the generation of reactive oxygen species, lipid peroxidation, mitochondrial complex-I activity, catalase activity, superoxide dismutase activity, glutathione content, Bax, caspase-3, Bcl-2 and tyrosine hydroxylase expression. Benzylpiperazine and benzoylpiperazine induced oxidative stress, inhibited mitochondrial functions and stimulated apoptosis. This study provides a germinal assessment of the neurotoxic mechanisms induced by piperazine derivatives that lead to neuronal cell death.

Repeated Mild Concussive Events Heighten the Vulnerability of Brain to Blast Exposure.

Mild concussive events without loss of consciousness are typically left untreated and can result in neurological abnormalities at later stages of life. No systematic studies have been carried out to determine the effect of concussion or repeated mild concussive episodes on brain vulnerability towards blast exposure. We have evaluated the effect of repeated mild concussive events on the vulnerability of brain to blast exposure using neurobehavioral functional assessments. Rats were subjected to either repeated mild concussive impacts (two impacts 1 week apart using a modified Marmarou weight drop model), a single blast exposure (19 psi using an advanced blast simulator), or a single blast exposure one day after the second mild concussive impact. Neurobehavioral changes were monitored using rotating pole test, open field exploration test, and novel object recognition test. Rotating pole test results indicated that vestibulomotor function was unaffected by blast or repeated mild concussive impacts, but significant impairment was observed in the blast exposed animals who had prior repeated mild concussive impacts. Novel object recognition test revealed short-term memory loss at 1 month post-blast only in rats subjected to both repeated mild concussive impacts and blast. Horizontal activity count, ambulatory activity count, center time and margin time legacies in the open field exploratory activity test indicated that only those rats exposed to both repeated mild concussive impacts and blast develop anxiety-like behaviors at both acute and sub-acute time-points. The results indicate that a history of repeated mild concussive episodes heightens brain vulnerability to blast exposure.

Clinical outcomes of chemotherapy in cancer patients with different ethnicities.

BACKGROUND: Choosing the most effective chemotherapeutic agent with safest side effect profile is a common challenge in cancer treatment. Although there are standardized chemotherapy protocols in place, protocol changes made after extensive clinical trials demonstrate significant improvement in the efficacy and tolerability of certain drugs. The pharmacokinetics, pharmacodynamics, and tolerance of anti-cancer medications are all highly individualized. A driving force behind these differences lies within a person's genetic makeup. RECENT FINDINGS: Pharmacogenomics, the study of how an individual's genes impact the processing and action of a drug, can optimize drug responsiveness and reduce toxicities by creating a customized medication regimen. However, these differences are rarely considered in the initial determination of standardized chemotherapeutic protocols and treatment algorithms. Because pharmacoethnicity is influenced by both genetic and nongenetic variables, clinical data highlighting disparities in the frequency of polymorphisms between different ethnicities is steadily growing.  Recent data suggests that ethnic variations in the expression of allelic variants may result in different pharmacokinetic properties of the anti-cancer medication. In this article, the clinical outcomes of various chemotherapy classes in patients of different ethnicities were reviewed. CONCLUSION: Genetic and nongenetic variables contribute to the interindividual variability in response to chemotherapeutic drugs. Considering pharmacoethnicity in the initial determination of standard chemotherapeutic protocols and treatment algorithms can lead to better clinical outcomes of patients of different ethnicities.

Upregulation of multiple toll-like receptors in ferret brain after blast exposure: Potential targets for treatment.

Although blast-induced traumatic brain injury (bTBI) has been designated as the signature injury of recent combat operations, its precise pathological mechanism(s) has not been identified thus far. Prior preclinical studies on bTBI demonstrated acute neuroinflammatory cascades which are known to be contributing to neurodegeneration. Danger-associated chemical patterns are released from the injured cells, which activate non-specific pattern recognition receptors, such as toll-like receptors (TLRs) leading to increased expression of inflammatory genes and release of cytokines. Upregulation of specific TLRs in the brain has been described as a mechanism of injury in diverse brain injury models unrelated to blast exposure. However, the expression profile of various TLRs in bTBI has not been investigated thus far. Hence, we have evaluated the expression of transcripts for TLR1-TLR10 in the brain of a gyrencephalic animal model of bTBI. We exposed ferrets to tightly coupled repeated blasts and determined the differential expression of TLRs (TLR1-10) by quantitative RT-PCR in multiple brain regions at 4 hr, 24 hr, 7 days and 28 days post-blast injury. The results obtained indicate that multiple TLRs are upregulated in the brain at 4 hr, 24 hr, 7 days and 28 days post-blast. Specifically, upregulation of TLR2, TLR4 and TLR9 was noted in different brain regions, suggesting that multiple TLRs might play a role in the pathophysiology of bTBI and that drugs that can inhibit multiple TLRs might have enhanced efficacy to attenuate brain damage and thereby improve bTBI outcome. Taken together, these results suggest that several TLRs are upregulated in the brain after bTBI and participate in the inflammatory response and thereby provide new insights into the disease pathogenesis. Therefore, inhibition of multiple TLRs, including TLR2, 4 and 9, simultaneously might be a potential therapeutic strategy for the treatment of bTBI.

Selective PPAR-Delta/PPAR-Gamma Activation Improves Cognition in a Model of Alzheimer's Disease.

Background: The continuously increasing association of Alzheimer's disease (AD) with increased mortality rates indicates an unmet medical need and the critical need for establishing novel molecular targets for therapeutic potential. Agonists for peroxisomal proliferator activating receptors (PPAR) are known to regulate energy in the body and have shown positive effects against Alzheimer's disease. There are three members of this class (delta, gamma, and alpha), with PPAR-gamma being the most studied, as these pharmaceutical agonists offer promise for AD because they reduce amyloid beta and tau pathologies, display anti-inflammatory properties, and improve cognition. However, they display poor brain bioavailability and are associated with several adverse side effects on human health, thus limiting their clinical application. Methods: We have developed a novel series of PPAR-delta and PPAR-gamma agonists in silico with AU9 as our lead compound that displays selective amino acid interactions focused upon avoiding the Tyr-473 epitope in the PPAR-gamma AF2 ligand binding domain. Results: This design helps to avoid the unwanted side effects of current PPAR-gamma agonists and improve behavioral deficits and synaptic plasticity while reducing amyloid-beta levels and inflammation in 3xTgAD animals. Conclusions: Our innovative in silico design of PPAR-delta/gamma agonists may offer new perspectives for this class of agonists for AD.

Blast Exposure Dysregulates Nighttime Melatonin Synthesis and Signaling in the Pineal Gland: A Potential Mechanism of Blast-Induced Sleep Disruptions.

Blast-induced traumatic brain injury (bTBI) frequently results in sleep-wake disturbances. However, limited studies have investigated the molecular signaling mechanisms underlying these sleep disturbances, and potentially efficacious therapies are lacking. We investigated the levels of melatonin and genes involved in melatonin synthesis pathway in the pineal glands of Sprague Dawley rats exposed to single and tightly coupled repeated blasts during the night and daytime. Rats were exposed to single and tightly coupled repeated blasts using an advanced blast simulator. The plasma, cerebrospinal fluid (CSF), and pineal gland were collected at 6 h, 24 h, or 1 month postblast at two different time points: one during the day (1000 h) and one at night (2200 h). Differential expressions of genes involved in pineal melatonin synthesis were quantified using quantitative real-time polymerase chain reaction (qRT-PCR). Plasma and CSF melatonin levels were assessed using a commercial melatonin ELISA kit. The plasma and CSF melatonin levels showed statistically significant decreases at 6 h and 24 h in the blast-exposed rats euthanized in the night (in dim light), with no significant alterations noted in rats euthanized in the morning (daylight) at all three-time points. Blast-exposed rats showed statistically significant decreases in Tph1, Aanat, Asmt, and Mtnr1b mRNA levels, along with increased Tph2 mRNA, in the pineal gland samples collected at night at 6 h and 24 h. No significant changes in the mRNA levels of these genes were noted at 1 month. These findings imply that the melatonin circadian rhythm is disrupted following blast exposure, which may be a factor in the sleep disturbances that blast victims frequently experience.

Role of Neddylation in Neurodegenerative Diseases.

Neurodegenerative diseases are characterized by progressive loss of neurons in specific regions of the brain. Neuronal death is often associated with the accumulation of misfolded proteins due to genetic mutations or abnormal protein homeostasis. An essential mechanism for regulating the clearance of misfolded proteins is neddylation, a post-translational modification closely related to ubiquitination. Neddylation is brought about by conjugating neural precursor cell-expressed developmentally downregulated protein 8 (NEDD8) to target substrates through a cascade of cellular events. Neddylation is crucial for many biological processes, and dysfunctional neddylation is implicated in several neurodegenerative diseases. This review discusses the current understanding of the role of neddylation pathways in neurodegenerative disorders and the emergence of neddylation signaling as a potential target for drug discovery and development in neurodegenerative diseases.

Impact of COVID-19 therapy on hyperglycemia.

The goal of this study was to analyze the effect of COVID-19 drugs and biologicals on hyperglycemia. A literature search with key terms, such as "COVID-19 drugs and hyperglycemia" and "COVID-19 vaccines and hyperglycemia," was conducted using PubMed through September 2021. The CDC data were referenced for current COVID-19 profile and statistics. The NIH COVID-19 guidelines were referenced for updated treatment recommendations. Micromedex and UpToDate were used for drug and disease information. Current results suggested that corticosteroids (dexamethasone), remdesivir and antivirals (lopinavir and ritonavir) all have the potential to significantly raise blood glucose levels putting patients at elevated risk for severe complications. In contrary, hydroxychloroquine is associated with hypoglycemia, and tocilizumab decreases inflammation which is associated with improving glucose levels. Other anti-cytokine bioactive molecules are correlated with lower blood glucose in patients with and without diabetes mellitus. Ivermectin, used for mild COVID-19 disease, possesses the potential for lowering blood glucose. Covishield, Pfizer-BioNTech, and Moderna have all been associated with hyperglycemia after the first dose. Individualized /personalized patient care is required for diabetic mellitus patients with COVID-19 infection. Improper drug therapy aggravates hyperglycemic conditions and other comorbid conditions, leading to increased morbidity and mortality.

Cardioprotective Effects of Oroxylum indicum Extract Against Doxorubicin and Cyclophosphamide-Induced Cardiotoxicity.

Administration of Chemotherapeutics, especially doxorubicin (DOX) and cyclophosphamide (CPS), is commonly associated with adverse effects such as myelosuppression and cardiotoxicity. At this time, few approved therapeutic options are currently available for the management of chemotherapy-associated cardiotoxicity. Thus, identification of novel therapeutics with potent cardioprotective properties and minimal adverse effects are pertinent in treating Doxorubicin and Cyclophosphamide-induced cardiotoxicity. Oroxylum indicum extract (OIE, Sabroxy®) is a natural product known to possess several beneficial biological functions including antioxidant, anti-inflammatory and cytoprotective effects. We therefore set to investigate the cardioprotective effects of OIE against Doxorubicin and Cyclophosphamide-induced cardiotoxicity and explore the potential cardioprotective mechanisms involved. Adult male mice were treated with DOX and CPS in combination, OIE alone, or a combination of OIE and DOX & CPS. Swimming test was performed to assess cardiac function. Markers of oxidative stress were assessed by levels of reactive oxygen species (ROS), nitrite, hydrogen peroxide, catalase, and glutathione content. The activity of interleukin converting enzyme and cyclooxygenase was determined as markers of inflammation. Mitochondrial function was assessed by measuring Complex-I activity. Apoptosis was assessed by Caspase-3 and protease activity. Mice treated with DOX and CPS exhibited reduced swim rate, increased oxidative stress, increased inflammation, and apoptosis in the heart tissue. These cardiotoxic effects were significantly reduced by co-administration of OIE. Furthermore, computational molecular docking studies revealed potential binding of DOX and CPS to tyrosine hydroxylase which validated our in vivo findings regarding the inhibition of tyrosine hydroxylase activity. Our current findings indicated that OIE counteracts Doxorubicin and Cyclophosphamide-induced cardiotoxicity-through inhibition of ROS-mediated apoptosis and by blocking the effect on tyrosine hydroxylase. Taken together, our findings suggested that OIE possesses cardioprotective effects to counteract potentially fatal cardiac complications associated with chemotherapy treatment.

COVID-19-induced cardiovascular damage differs from other prevalent viruses.

Viral infections persist globally, among all ages, gender, and ethnicity. Of particular importance is COVID-19, associated with asymptomatic to severe symptoms, including complications/mortality. Cardiovascular disease (CVD) involves heart and blood vessel disorders including coronary heart disease, cerebrovascular disease, peripheral artery disease, thrombosis, and more. CVD associated with severe COVID-19 includes heart failure, coronary artery disease, cardiomyopathy, hypertension, and cerebrovascular disease/stroke. Data were acquired from PubMed, Google Scholar, Centers for Disease Prevention and Control, and Lexi-Comp using the search terms "COVID-19 and cardiovascular pathology;" "COVID-19 induced CVD;" "Viral infection induced CVD;" and "Viral infection induced heart damage." COVID-19-induced CVD mechanisms include direct viral entry, inflammation, cytokine storm, hypoxia, interferon-mediated immune response, plaque destabilization, stress, and drug-induced causes. Other viral pathologies causing CVD include atherosclerosis, inflammation, cytokine storm, and plaque destabilization. Individual parameters, such as old age, males, and higher body mass index (BMI), are more likely to experience viral-associated complications, possibly explained by patient risk factors or comorbidities. Populations at higher risk include older males with an elevated BMI. Viral mechanisms associated with CVD are similar but differ in disease severity, potentially explained by diverse cytokine profiles where COVID-19 activates different types at higher quantities.

Caffeine, a natural methylxanthine nutraceutical, exerts dopaminergic neuroprotection.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects more than 10 million people worldwide. Oxidative stress and mitochondrial dysfunction play a significant role in altering the homeostasis of energy production and free radical generation. Current PD therapies are focused on reducing the cardinal symptoms rather than preventing disease progression in the patients. Adenosine A2A receptor (A2A R) antagonist (Istradephylline) combined with levodopa shows a promising therapy for PD. In animal studies, caffeine administration showed to improve motor functions and neuroprotective effect in the neurons. Caffeine is probably the most extensively used psychoactive substance. In this current study, we investigated the neuroprotective effect of caffeine against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurodegeneration. Here, we demonstrate that caffeine improves behavioral and neurotransmitter recovery against MPTP-induced toxicity. Caffeine restores endogenous antioxidant levels and suppresses neuroinflammation. Our finding suggests that the blockage of A2AR is a promising disease-modifying therapy for PD. Target engagement strategies could be more beneficial in preventing disease progression rather than symptomatic reliefs in PD patients.

Effects of prenatal synthetic cannabinoid exposure on the cerebellum of adolescent rat offspring.

Cannabis is the most commonly used illicit drug worldwide. Recently, cannabis use among young pregnant women has greatly increased. However, prenatal cannabinoid exposure leads to long-lasting cognitive, motor, and behavioral deficits in the offspring and alterations in neural circuitry through various mechanisms. Although these effects have been studied in the hippocampus, the effects of prenatal cannabinoid exposure on the cerebellum are not well elucidated. The cerebellum plays an important role in balance and motor control, as well as cognitive functions such as attention, language, and procedural memories. The aim of this study was to investigate the effects of prenatal cannabinoid exposure on the cerebellum of adolescent offspring. Pregnant rats were treated with synthetic cannabinoid agonist WIN55,212-2, and the offspring were evaluated for various cerebellar markers of oxidative stress, mitochondrial function, and apoptosis. Additionally, signaling proteins associated with glutamate dependent synaptic plasticity were examined. Administration of WIN55,212-2 during pregnancy altered markers of oxidative stress by significantly reducing oxidative stress and nitrite content. Mitochondrial Complex I and Complex IV activities were also enhanced following prenatal cannabinoid exposure. With regard to apoptosis, pP38 levels were significantly increased, and proapoptotic factor caspase-3 activity, pERK, and pJNK levels were significantly decreased. CB1R and GluA1 levels remained unchanged; however, GluN2A was significantly reduced. There was a significant decrease in MAO activity although tyrosine hydroxylase activity was unaltered. Our study indicates that the effects of prenatal cannabinoid exposure on the cerebellum are unique compared to other brain regions by enhancing mitochondrial function and promoting neuronal survival. Further studies are required to evaluate the mechanisms by which prenatal cannabinoid exposure alters cerebellar processes and the impact of these alterations on behavior.