Role of Calcitriol and Vitamin D Receptor (VDR) Gene Polymorphisms in Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by amyloid beta (Aß) buildup and neuronal degeneration. An association between low serum vitamin D levels and an increased risk of AD has been reported in several epidemiological studies. Calcitriol (1,25-dihydroxycholecalciferol) is the active form of vitamin D, and is generated in the kidney and many other tissues/organs, including the brain. It is a steroid hormone that regulates important functions like calcium/phosphorous levels, bone mineralization, and immunomodulation, indicating its broader systemic significance. In addition, calcitriol confers neuroprotection by mitigating oxidative stress and neuroinflammation, promoting the clearance of Aß, myelin formation, neurogenesis, neurotransmission, and autophagy. The receptors to which calcitriol binds (vitamin D receptors; VDRs) to exert its effects are distributed over many organs and tissues, representing other significant roles of calcitriol beyond sustaining bone health. The biological effects of calcitriol are manifested through genomic (classical) and non-genomic actions through different pathways. The first is a slow genomic effect involving nuclear VDR directly affecting gene transcription. The association of AD with VDR gene polymorphisms relies on the changes in vitamin D consumption, which lowers VDR expression, protein stability, and binding affinity. It leads to the altered expression of genes involved in the neuroprotective effects of calcitriol. This review summarizes the neuroprotective mechanism of calcitriol and the role of VDR polymorphisms in AD, and might help develop potential therapeutic strategies and markers for AD in the future.

Multi-Targeting Neuroprotective Effects of Syzygium aromaticum Bud Extracts and Their Key Phytocompounds against Neurodegenerative Diseases.

Alzheimer's disease (AD) is a neurodegenerative disease that causes a gradual loss of normal motor and cognitive function. The complex AD pathophysiology involves various factors such as oxidative stress, neuroinflammation, amyloid-beta (Aß) aggregation, disturbed neurotransmission, and apoptosis. The available drugs suffer from a range of side effects and are not able to cover different aspects of the disease. Therefore, finding a safer therapeutic approach that can affect multiple targets at a time is highly desirable. In the present study, the underlying neuroprotective mechanism of an important culinary spice, Syzygium aromaticum (Clove) extract, and major bioactive compounds were studied in hydrogen peroxide-induced oxidative stress in human neuroblastoma SH-SY5Y cell lines as a model. The extracts were subjected to GC-MS to identify important bioactive components. The extracts and key bio-actives reduced reactive oxygen species (ROS), restored mitochondrial membrane potential (MMP), and provided neuroprotection from H2O2-induced oxidative stress in cell-based assays due to the antioxidant action. They also reduced lipid peroxidation significantly and restored GSH content. Clove extracts have also displayed anti-acetylcholinesterase (AChE) activity, anti-glycation potential, and Aß aggregation/fibrilization inhibition. The multitarget neuroprotective approach displayed by Clove makes it a potential candidate for AD drug development.

Withanolides from Withania somnifera Ameliorate Neutrophil Infiltration in Endotoxin-Induced Peritonitis by Regulating Oxidative Stress and Inflammatory Cytokines.

Identification of novel anti-inflammatory strategies are needed to avoid the side effects associated with the currently available therapies. Use of anti-inflammatory herbal remedies is gaining attention. The purpose of the present investigation was to evaluate the pharmacological potential of the withanolide-rich root extracts of the medical plant Withania somnifera (L.) Dunal using in vivo and in vitro models of endotoxin-induced inflammation and oxidative stress. The pharmacological effects of W. somnifera root extracts were evaluated using a mouse model of endotoxin (lipopolysaccharide)-induced peritonitis and various relevant human cell lines. HPLC analysis of the W. somnifera root extracts identified the presence of various bioactive withanolides. In vivo challenge of mice with endotoxin resulted in the infiltration of various leukocytes, specifically neutrophils, along with monocytes and lymphocytes into the peritoneal cavity. Importantly, prophylactic treatment with W. somnifera inhibited the migration of neutrophils, lymphocytes, and monocytes and decreased the release of interleukin-1ß, TNF-α, and interleukin-6 cytokines into the peritoneal cavity as identified by ELISA. Liver (glutathione peroxidase, glutathione, glutathione disulfide, superoxide dismutase, malondialdehyde, myeloperoxidase) and peritoneal fluid (nitrite) biochemical analysis revealed the antioxidant profile of W. somnifera. Similarly, in human HepG2 cells, W. somnifera significantly modulated the antioxidant levels. In THP-1 cells, W. somnifera decreased the secretion of interleukin-6 and TNF-α. In HEK-Blue reporter cells, W. somnifera inhibited TNF-α-induced nuclear factor-κB/activator protein 1 transcriptional activity. Our findings suggest the pharmacological effects of root extracts of W. somnifera rich in withanolides inhibit neutrophil infiltration, oxidative hepatic damage, and cytokine secretion via modulating the nuclear factor-κB/activator protein 1 pathway.

Nucleic acid analysis on paper substrates (NAAPs): an innovative tool for Point of Care (POC) infectious disease diagnosis.

The cost-effective rapid diagnosis of infectious diseases is an essential and important factor for curing such diseases in the global public health care picture. Owing to poor infrastructure and lack of sanitation, these diseases have an extreme impact on remote and rural areas, especially in developing countries, and there are unresolved challenges. Molecular diagnosis, such as nucleic acid analysis, plays a key role in the significant treatment of numerous infectious diseases. Current molecular diagnostic assays require a sophisticated laboratory setup with expensive components. Molecular diagnosis on a microfluidic point-of-care (POC) platform is attractive to researchers for disease detection with proper prevention. Compared to various microfluidic substrate materials, paper-based POC technologies offer significant cost-effective solutions over high-cost clinical instruments to fill the gap between the needs of users and affordability. Low-cost paper-based microfluidic POC technologies provide portable and disposable diagnostic systems for multiple disease detection that may be extremely useful in remote areas. This article presents a critical review of paper-based microfluidic device technology which has become an imminent platform to adjust the current health scenario for the detection of diseases using different stages of nucleic acid analysis, such as extraction, amplification and detection of nucleic acid, with future perspectives for paper substrates.

Phytosterols: Potential Metabolic Modulators in Neurodegenerative Diseases.

Phytosterols constitute a class of natural products that are an important component of diet and have vast applications in foods, cosmetics, and herbal medicines. With many and diverse isolated structures in nature, they exhibit a broad range of biological and pharmacological activities. Among over 200 types of phytosterols, stigmasterol and ß-sitosterol were ubiquitous in many plant species, exhibiting important aspects of activities related to neurodegenerative diseases. Hence, this mini-review presented an overview of the reported studies on selected phytosterols related to neurodegenerative diseases. It covered the major phytosterols based on biosynthetic considerations, including other phytosterols with significant in vitro and in vivo biological activities.

Adolescent With von Willebrand Disease Type 3 Spontaneous Abdominal Hemorrhage.

An adolescent female classified as unstable with a spontaneous abdominal hemorrhage was transferred to a level 1 pediatric trauma tertiary emergency department. Pertinent medical history included von Willebrand disease type 3, menorrhagia, and obesity. Preparation before patient arrival included mobilization of multidisciplinary medical team experts in hematology, pharmacy, blood bank, radiology, and nursing who provided lifesaving interventions. The administration of factor products, blood products, interventional radiology, emergent hepatic angiography, and embolization coordination resulted in a successful outcome. After an 18-day intensive hospital course, the patient returned home close to her baseline health status.

Identification of diphenylalkylisoxazol-5-amine scaffold as novel activator of cardiac myosin.

To identify novel potent cardiac myosin activator, a series of diphenylalkylisoxazol-5-amine compounds 4-7 have been synthesized and evaluated for cardiac myosin ATPase activation. Among the 37 compounds, 4a (CMA at 10 µM = 81.6%), 4w (CMA at 10 µM = 71.2%) and 6b (CMA at 10 µM = 67.4%) showed potent cardiac myosin activation at a single concentration of 10 µM. These results suggested that the introduction of the amino-isoxazole ring as a bioisostere for urea group is acceptable for the cardiac myosin activation. Additional structure-activity relationship (SAR) studies were conducted. Para substitution (-Cl, -OCH3, -SO2N(CH3)2) to the phenyl rings or replacement of a phenyl ring with a heterocycle (pyridine, piperidine and tetrahydropyran) appeared to attenuate cardiac myosin activation at 10 µM. Additional hydrogen bonding acceptor next to the amino group of the isoxazoles did not enhance the activity. The potent isoxazole compounds showed selectivity for cardiac myosin activation over skeletal and smooth muscle myosin, and therefore these potent and selective isoxazole compounds could be considered as a new series of cardiac myosin ATPase activators for the treatment of systolic heart failure.

Design and synthesis of sulfonamidophenylethylamides as novel cardiac myosin activator.

The sulfonamidophenylethylamide analogues were explored for finding novel and potent cardiac myosin activators. Among them, N-(4-(N,N-dimethylsulfamoyl)phenethyl-N-methyl-5-phenylpentanamide (13, CMA at 10 µM = 48.5%; FS = 26.21%; EF = 15.28%) and its isomer, 4-(4-(N,N-dimethylsulfamoyl)phenyl-N-methyl-N-(3-phenylpropyl)butanamide (27, CMA at 10 µM = 55.0%; FS = 24.69%; EF = 14.08%) proved to be efficient cardiac myosin activators both in in vitro and in vivo studies. Compounds 13 (88.2 + 3.1% at 5 µM) and 27 (46.5 + 2.8% at 5 µM) showed positive inotropic effect in isolated rat ventricular myocytes. The potent compounds 13 and 27 were highly selective for cardiac myosin over skeletal and smooth muscle myosin, and therefore these potent and selective amide derivatives could be considered a new class of cardiac myosin activators for the treatment of systolic heart failure.

Colchicine: Isolation, LC-MS QTof Screening, and Anticancer Activity Study of Gloriosa superba Seeds.

Colchicine was extracted from Gloriosa superba seeds using the Super Critical Fluid (CO2) Extraction (SCFE) technology. The seeds were purified upto 99.82% using column chromatography. Colchicine affinity was further investigated for anticancer activity in six human cancer cell lines, i.e., A549, MCF-7, MDA-MB231, PANC-1, HCT116, and SiHa. Purified colchicine showed the least cell cytotoxicity and antiproliferation and caused no G2/M arrest at clinically acceptable concentrations. Mitotic arrest was observed in only A549 and MDA-MB231 cell lines at 60nM concentration. Our finding indicated the possible use of colchicine at a clinically acceptable dose and provided insight into the science behind microtubule destabilization. However, more studies need to be conducted beforethese findings could be established.

Exploration of diphenylalkyloxadiazoles as novel cardiac myosin activator.

To explore novel cardiac myosin activator, a series of diphenylalkyl substituted 1,3,4-oxadiazoles and 1,2,4-oxadiazoles have been prepared and tested for cardiac myosin ATPase activation in vitro. In all cases, three carbon spacer between the oxadiazole core and one of the phenyl ring was considered crucial. In case of 1,3,4-oxadiazole, zero to two carbon spacer between oxadiazole core and other phenyl ring are favorable. Phenyl ring can be replaced by cyclohexyl moiety. In case of 1,2,4-oxadiazole, zero or one carbon spacer between the oxadiazole and other phenyl ring are favorable. Introduction of hydrogen bonding donor (NH) group at the 2nd position of the 1,3,4-oxadiazole enhances the activity. Substitutions on either of the phenyl rings or change of phenyl ring to other heterocycle are not tolerated for both the oxadiazoles. The prepared oxadiazoles showed selective activation for cardiac muscle over smooth and skeleton muscles.

Molecular and Cellular Toxicology of Nanomaterials with Related to Aquatic Organisms.

The increasing application of nanomaterials both in commercial and industrial products has led their accumulation in the aquatic ecosystem. The rapid development and large scale production of nanomaterials in the last few decades have stimulated concerns regarding their potential environmental health risks on aquatic biota. Inorganic nanoparticles, due to their unique properties and associated material characteristics resulted in toxicity of these nanomaterials in aquatic organisms. Understanding their novel properties at nanoscale has established to be a significant aspect of their toxicity. Unique properties such as size, surface area, surface coating, surface charge, aggregation of particles and dissolution may affect cellular uptake, molecular response, in vivo reactivity and delivery across tissues of living organism. Already lot of research in the past three or four decades within the nano-ecotoxicology field had been carried out. However, there is not any standard technique yet to assess toxicity of nanoparticles (NPs) on different biological systems such as reproductive, respiratory, nervous, gastrointestinal systems, and development stages of aquatic organisms. Specific toxicological techniques and quantification of nanoparticles are vital to establish regulations to control their impact on the aquatic organism and their release in the aquatic environment. The main aim of this chapter is to critically evaluate the current literature on the toxicity of nanomaterials on aquatic organism.

Black Pepper (Piper nigrum) Alleviates Oxidative Stress, Exerts Potential Anti-Glycation and Anti-AChE Activity: A Multitargeting Neuroprotective Agent against Neurodegenerative Diseases.

Neurodegenerative diseases (NDs) are a family of disorders that cause progressive structural and functional degeneration of neurons. Among all the organs in the body, the brain is the one that is the most affected by the production and accumulation of ROS. Various studies have shown that an increase in oxidative stress is a common pathophysiology for almost all NDs, which further affects various other pathways. The available drugs lack the wide spectrum necessary to confront these complexities altogether. Hence, a safe therapeutic approach to target multiple pathways is highly desirable. In the present study, the hexane and ethyl acetate extracts of Piper nigrum (black pepper), an important spice, were evaluated for their neuroprotective potential in hydrogen peroxide-induced oxidative stress in human neuroblastoma cells (SH-SY5Y). The extracts were also subjected to GC/MS to identify the important bioactives present. The extracts exhibited neuroprotection by significantly decreasing the oxidative stress and restoring the mitochondrial membrane potential in the cells. Additionally, the extracts displayed potent anti-glycation and significant anti-Aß fibrilization activities. The extracts were competitive inhibitors of AChE. The multitarget neuroprotective mechanism displayed by Piper nigrum indicates it as a potential candidate in the treatment of NDs.

Unique Bioactives from Zombie Fungus (Cordyceps) as Promising Multitargeted Neuroprotective Agents.

Cordyceps, also known as "zombie fungus", is a non-poisonous mushroom that parasitizes insects for growth and development by manipulating the host system in a way that makes the victim behave like a "zombie". These species produce promising bioactive metabolites, like adenosine, ß-glucans, cordycepin, and ergosterol. Cordyceps has been used in traditional medicine due to its immense health benefits, as it boosts stamina, appetite, immunity, longevity, libido, memory, and sleep. Neuronal loss is the typical feature of neurodegenerative diseases (NDs) (Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS)) and neurotrauma. Both these conditions share common pathophysiological features, like oxidative stress, neuroinflammation, and glutamatergic excitotoxicity. Cordyceps bioactives (adenosine, N6-(2-hydroxyethyl)-adenosine, ergosta-7, 9 (11), 22-trien-3ß-ol, active peptides, and polysaccharides) exert potential antioxidant, anti-inflammatory, and anti-apoptotic activities and display beneficial effects in the management and/or treatment of neurodegenerative disorders in vitro and in vivo. Although a considerable list of compounds is available from Cordyceps, only a few have been evaluated for their neuroprotective potential and still lack information for clinical trials. In this review, the neuroprotective mechanisms and safety profile of Cordyceps extracts/bioactives have been discussed, which might be helpful in the identification of novel potential therapeutic entities in the future.

Trachyspermum ammi Bioactives Promote Neuroprotection by Inhibiting Acetylcholinesterase, Aß-Oligomerization/Fibrilization, and Mitigating Oxidative Stress In Vitro.

Neurodegenerative diseases (NDs) are a large category of progressive neurological disorders with diverse clinical and pathological characteristics. Among the NDs, Alzheimer's disease (AD) is the most widespread disease, which affects more than 400 million people globally. Oxidative stress is evident in the pathophysiology of nearly all NDs by affecting several pathways in neurodegeneration. No single drug can manage multi-faceted diseases like NDs. Therefore, an alternative therapeutic strategy is required, which can affect several pathophysiological pathways at a time. To achieve this aim, hexane and ethyl acetate extract from Trachyspermum ammi (Carom) were prepared, and GC/MS identified the bioactive compounds. For the cell-based assays, oxidative stress was induced in SH-SY5Y neuroblastoma cells using hydrogen peroxide to evaluate the neuroprotective potential of the Carom extracts/bioactives. The extracts/bioactives provided neuroprotection in the cells by modulating multiple pathways involved in neurodegeneration, such as alleviating oxidative stress and mitochondrial membrane potential. They were potent inhibitors of acetylcholine esterase enzymes and displayed competitive/mixed-type inhibition. Additionally, anti-Aß1-42 fibrilization/oligomerization and anti-glycation activities were also analyzed. The multi-faceted neuroprotection shown via Carom/Carvacrol makes it a prospective contender in drug development for NDs.

Study on anti-proliferative effect of benzoxathiole derivatives through inactivation of NF-κB in human cancer cells.

To investigate the anti-proliferative effect of a newly discovered NF-kB inhibitor, 6,6-dimethyl-2-(phenylimino)-6,7-dihydrobenzo[d][1,3]oxathiol-4(5H)-one (1a), a series of its analogs (1b-n) were prepared and evaluated for their NF-κB inhibition and anti-proliferative activity against various human cancer cell lines. Slight variation of hydrophobicity by replacement of dimethyl group of 1a at 6-position with bulky isopropyl group and introduction of para-fluoro substitution on 2-phenyl group showed good NF-κB inhibitory activity and anti-proliferative activity. However, excessive increase in hydrophobicity with 2,4,6-trichloro substituents on phenyl group resulted in the loss of both the activities. From the SAR results, 2-phenylimino-6,7-dihydrobenzo[d][1,3]oxathiol-4(5H)-one was identified as the lead scaffold for investigating new anticancer agent through inactivation of NF-κB.

Multi-Target Approach of Murraya koenigii Leaves in Treating Neurodegenerative Diseases.

Neurodegenerative diseases (NDs) mainly affect neurons and gradually lead to a loss of normal motor and cognitive functions. Atypical protein homeostasis-misfolding, aggregations and accumulations, oxidative stress, inflammation, and apoptosis-are common features in most NDs. To date, due to the complex etiology and pathogenesis of NDs, no defined treatment is available. There has been increasing interest in plant extracts as potential alternative medicines as the presence of various active components may exert synergistic and multi-pharmacological effects. Murraya koenigii (Rutaceae) is utilized in Ayurvedic medicine for various ailments. Pharmacological studies evidenced its potential antioxidant, anti-inflammatory, anticancer, hepatoprotective, immunomodulatory, antimicrobial, and neuroprotective activities, among others. In line with our interest in exploring natural agents for the treatment of neurodegenerative diseases, this review presents an overview of literature concerning the mechanisms of action and the safety profile of significant bioactive components present in M. koenigii leaves to support further investigations into their neuroprotective therapeutic potential.

Phyto-Carbazole Alkaloids from the Rutaceae Family as Potential Protective Agents against Neurodegenerative Diseases.

Plant-derived (phyto) carbazole alkaloids are an important class of compounds, presented in the family of Rutaceae (Genera Murraya, Clausena, Glycosmis, Micromelum and Zanthoxylum). Due to several significant biological activities, such as antitumor, antibacterial, antiviral, antidiabetic, anti-HIV and neuroprotective activities of the parent skeleton (3-methylcarbazole), carbazole alkaloids are recognized as an important class of potential therapeutic agents. Neurodegenerative diseases (NDs) may exhibit a vast range of conditions, affecting neurons primarily and leading ultimately to the progressive losses of normal motor and cognitive functions. The main pathophysiological indicators of NDs comprise increasing atypical protein folding, oxidative stresses, mitochondrial dysfunctions, deranged neurotransmissions and neuronal losses. Phyto-carbazole alkaloids can be investigated for exerting multitarget approaches to ameliorating NDs. This review presents a comprehensive evaluation of the available scientific literature on the neuroprotective mechanisms of phyto-carbazole alkaloids from the Rutaceae family in ameliorating NDs.

Prion therapeutics: Lessons from the past.

Prion diseases are a group of incurable zoonotic neurodegenerative diseases (NDDs) in humans and other animals caused by the prion proteins. The abnormal folding and aggregation of the soluble cellular prion proteins (PrPC) into scrapie isoform (PrPSc) in the Central nervous system (CNS) resulted in brain damage and other neurological symptoms. Different therapeutic approaches, including stalling PrPC to PrPSc conversion, increasing PrPSc removal, and PrPC stabilization, for which a spectrum of compounds, ranging from organic compounds to antibodies, have been explored. Additionally, a non-PrP targeted drug strategy using serpin inhibitors has been discussed. Despite numerous scaffolds being screened for anti-prion activity in vitro, only a few were effective in vivo and unfortunately, almost none of them proved effective in the clinical studies, most likely due to toxicity and lack of permeability. Recently, encouraging results from a prion-protein monoclonal antibody, PRN100, were presented in the first human trial on CJD patients, which gives a hope for better future for the discovery of other new molecules to treat prion diseases. In this comprehensive review, we have re-visited the history and discussed various classes of anti-prion agents, their structure, mode of action, and toxicity. Understanding pathogenesis would be vital for developing future treatments for prion diseases. Based on the outcomes of existing therapies, new anti-prion agents could be identified/synthesized/designed with reduced toxicity and increased bioavailability, which could probably be effective in treating prion diseases.

Mechanistic Insights into the Neuroprotective Potential of Sacred Ficus Trees.

Ficus religiosa (Bo tree or sacred fig) and Ficus benghalensis (Indian banyan) are of immense spiritual and therapeutic importance. Various parts of these trees have been investigated for their antioxidant, antimicrobial, anticonvulsant, antidiabetic, anti-inflammatory, analgesic, hepatoprotective, dermoprotective, and nephroprotective properties. Previous reviews of Ficus mostly discussed traditional usages, photochemistry, and pharmacological activities, though comprehensive reviews of the neuroprotective potential of these Ficus species extracts and/or their important phytocompounds are lacking. The interesting phytocompounds from these trees include many bengalenosides, carotenoids, flavonoids (leucopelargonidin-3-O-ß-d-glucopyranoside, leucopelargonidin-3-O-α-l-rhamnopyranoside, lupeol, cetyl behenate, and α-amyrin acetate), flavonols (kaempferol, quercetin, myricetin), leucocyanidin, phytosterols (bergapten, bergaptol, lanosterol, ß-sitosterol, stigmasterol), terpenes (α-thujene, α-pinene, ß-pinene, α-terpinene, limonene, ß-ocimene, ß-bourbonene, ß-caryophyllene, α-trans-bergamotene, α-copaene, aromadendrene, α-humulene, alloaromadendrene, germacrene, γ-cadinene, and δ-cadinene), and diverse polyphenols (tannin, wax, saponin, leucoanthocyanin), contributing significantly to their pharmacological effects, ranging from antimicrobial action to neuroprotection. This review presents extensive mechanistic insights into the neuroprotective potential, especially important phytochemicals from F. religiosa and F. benghalensis. Owing to the complex pathophysiology of neurodegenerative disorders (NDDs), the currently existing drugs merely alleviate the symptoms. Hence, bioactive compounds with potent neuroprotective effects through a multitarget approach would be of great interest in developing pharmacophores for the treatment of NDDs.

Vinpocetine, a PDE1 modulator, regulates markers of cerebral health, inflammation, and oxidative stress in a rat model of prenatal alcohol-induced experimental attention deficit hyperactivity disorder.

Prenatal alcohol exposure (PAE) has been shown to induce symptomatology associated with attention deficit hyperactivity disorder (ADHD) by altering neurodevelopmental trajectories. Phosphodiesterase-1 (PDE1) is expressed centrally and has been used in various experimental brain conditions. We investigated the role of vinpocetine, a PDE1 inhibitor, on behavioral phenotypes and important biochemical deficits associated with a PAE rat model of ADHD. Protein markers of cerebral health (synapsin-IIa, BDNF, and pCREB), inflammation (IL-6, IL-10, and TNF-α), and oxidative stress (TBARS, GSH, and SOD) were analyzed in three brain regions (frontal cortex, striatum, and cerebellum). Hyperactivity, inattention, and anxiety introduced in the offspring due to PAE were assayed using open-field, Y-maze, and elevated plus maze, respectively. Administration of vinpocetine (10 & 20 mg/kg, p.o. [by mouth]) to PAE rat offspring for 4 weeks resulted in improvement of the behavioral profile of the animals. Additionally, levels of protein markers such as synapsin-IIa, BDNF, pCREB, IL-10, SOD, and GSH were found to be significantly increased, with a significant reduction in markers such as TNF-α, IL-6, and TBARS in selected brain regions of vinpocetine-treated animals. Vinpocetine, a selective PDE1 inhibitor, rectified behavioral phenotypes associated with ADHD, possibly by improving cerebral function, reducing brain inflammation, and reducing brain oxidative stress. This study provides preliminary analysis and suggests that the PDE1 enzyme may be an important pharmacological tool to study ADHD as a result of PAE.