Publications by authors named "Shreesh K Ojha"

21 Publications

  • Page 1 of 1

Thymoquinone, a Dietary Bioactive Compound, Exerts Anti-Inflammatory Effects in Colitis by Stimulating Expression of the Colonic Epithelial PPAR-γ Transcription Factor.

Nutrients 2021 Apr 17;13(4). Epub 2021 Apr 17.

Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain PO Box 17666, United Arab Emirates.

Inflammatory bowel diseases (IBD) are chronic inflammatory disorders with increasing incidence and prevalence worldwide. Here, we investigated thymoquinone (TQ), a naturally occurring phytochemical present in , for anti-inflammatory effects in colonic inflammation. To address this, we used in vivo (mice) and in vitro (HT-29 cells) models in this investigation. Our results showed that TQ treatment significantly reduced the disease activity index (DAI), myeloperoxidase (MPO) activity, and protected colon microscopic architecture. In addition, TQ also reduced the expression of proinflammatory cytokines and mediators at both the mRNA and protein levels. Further, TQ decreased phosphorylation of the activated mitogen-activated protein kinase (MAPK) signaling pathway and nuclear factor kappa B (NF-κB) proteins and enhanced colon epithelial PPAR-γ transcription factor expression. TQ significantly decreased proinflammatory chemokines (CXCL-1 and IL-8), and mediator (COX-2) mRNA expression in HT-29 cells treated with TNF-α. TQ also increased HT-29 PPAR-γ mRNA, PPAR-γ protein expression, and PPAR-γ promoter activity. These results indicate that TQ inhibits MAPK and NF-κB signaling pathways and transcriptionally regulates PPAR-γ expression to induce potent anti-inflammatory activity in vivo and in vitro models of colon inflammation.
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http://dx.doi.org/10.3390/nu13041343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073634PMC
April 2021

Valeric Acid Protects Dopaminergic Neurons by Suppressing Oxidative Stress, Neuroinflammation and Modulating Autophagy Pathways.

Int J Mol Sci 2020 Oct 16;21(20). Epub 2020 Oct 16.

Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, UAE.

Parkinson's disease, the second common neurodegenerative disease is clinically characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) with upregulation of neuroinflammatory markers and oxidative stress. Autophagy lysosome pathway (ALP) plays a major role in degradation of damaged organelles and proteins for energy balance and intracellular homeostasis. However, dysfunction of ALP results in impairment of α-synuclein clearance which hastens dopaminergic neurons loss. In this study, we wanted to understand the neuroprotective efficacy of Val in rotenone induced PD rat model. Animals received intraperitoneal injections (2.5 mg/kg) of rotenone daily followed by Val (40 mg/kg, i.p) for four weeks. Valeric acid, a straight chain alkyl carboxylic acid found naturally in have been used in the treatment of neurological disorders. However, their neuroprotective efficacy has not yet been studied. In our study, we found that Val prevented rotenone induced upregulation of pro-inflammatory cytokine oxidative stress, and α-synuclein expression with subsequent increase in vital antioxidant enzymes. Moreover, Val mitigated rotenone induced hyperactivation of microglia and astrocytes. These protective mechanisms prevented rotenone induced dopaminergic neuron loss in SNpc and neuronal fibers in the striatum. Additionally, Val treatment prevented rotenone blocked mTOR-mediated p70S6K pathway as well as apoptosis. Moreover, Val prevented rotenone mediated autophagic vacuole accumulation and increased lysosomal degradation. Hence, Val could be further developed as a potential therapeutic candidate for treatment of PD.
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http://dx.doi.org/10.3390/ijms21207670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589299PMC
October 2020

Neuroprotective Effect of Curcumin on the Nigrostriatal Pathway in a 6-Hydroxydopmine-Induced Rat Model of Parkinson's Disease is Mediated by α7-Nicotinic Receptors.

Int J Mol Sci 2020 Oct 3;21(19). Epub 2020 Oct 3.

Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain PO BOX 17666, UAE.

Parkinson's disease (PD) is a common neurodegenerative disorder, characterized by selective degeneration of dopaminergic nigrostriatal neurons. Most of the existing pharmacological approaches in PD consider replenishing striatal dopamine. It has been reported that activation of the cholinergic system has neuroprotective effects on dopaminergic neurons, and human α7-nicotinic acetylcholine receptor (α7-nAChR) stimulation may offer a potential therapeutic approach in PD. Our recent in-vitro studies demonstrated that curcumin causes significant potentiation of the function of α7-nAChRs expressed in oocytes. In this study, we conducted in vivo experiments to assess the role of the α7-nAChR on the protective effects of curcumin in an animal model of PD. Intra-striatal injection of 6-hydroxydopmine (6-OHDA) was used to induce Parkinsonism in rats. Our results demonstrated that intragastric curcumin treatment (200 mg/kg) significantly improved the abnormal motor behavior and offered neuroprotection against the reduction of dopaminergic neurons, as determined by tyrosine hydroxylase (TH) immunoreactivity in the substantia nigra and caudoputamen. The intraperitoneal administration of the α7-nAChR-selective antagonist methyllycaconitine (1 µg/kg) reversed the neuroprotective effects of curcumin in terms of both animal behavior and TH immunoreactivity. In conclusion, this study demonstrates that curcumin has a neuroprotective effect in a 6-hydroxydopmine (6-OHDA) rat model of PD via an α7-nAChR-mediated mechanism.
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http://dx.doi.org/10.3390/ijms21197329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583812PMC
October 2020

Therapeutic Potential of β-Caryophyllene: A Dietary Cannabinoid in Diabetes and Associated Complications.

Nutrients 2020 Sep 28;12(10). Epub 2020 Sep 28.

Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 17666, UAE.

Diabetes mellitus (DM), a metabolic disorder is one of the most prevalent chronic diseases worldwide across developed as well as developing nations. Hyperglycemia is the core feature of the type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), following insulin deficiency and impaired insulin secretion or sensitivity leads insulin resistance (IR), respectively. Genetic and environmental factors attributed to the pathogenesis of DM and various therapeutic strategies are available for the prevention and treatment of T2DM. Among the numerous therapeutic approaches, the health effects of dietary/nutraceutical approach due to the presence of bioactive constituents, popularly termed phytochemicals are receiving special interest for pharmacological effects and therapeutic benefits. The phytochemicals classes, in particular sesquiterpenes received attention because of potent antioxidant, anti-inflammatory, and antihyperglycemic effects and health benefits mediating modulation of enzymes, receptors, and signaling pathways deranged in DM and its complications. One of the terpene compounds, β-caryophyllene (BCP), received enormous attention because of its abundant occurrence, non-psychoactive nature, and dietary availability through consumption of edible plants including spices. BCP exhibit selective full agonism on cannabinoid receptor type 2 (CB2R), an important component of endocannabinoid system, and plays a role in glucose and lipid metabolism and represents the newest drug target for chronic inflammatory diseases. BCP also showed agonist action on peroxisome proliferated activated receptor subtypes, PPAR-α and PPAR-γ, the main target of currently used fibrates and imidazolidinones for dyslipidemia and IR, respectively. Many studies demonstrated its antioxidant, anti-inflammatory, organoprotective, and antihyperglycemic properties. In the present review, the plausible therapeutic potential of BCP in diabetes and associated complications has been comprehensively elaborated based on experimental and a few clinical studies available. Further, the pharmacological and molecular mechanisms of BCP in diabetes and its complications have been represented using synoptic tables and schemes. Given the safe status, abundant natural occurrence, oral bioavailability, dietary use and pleiotropic properties modulating receptors and enzymes, BCP appears as a promising molecule for diabetes and its complications.
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http://dx.doi.org/10.3390/nu12102963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599522PMC
September 2020

Nerolidol Mitigates Colonic Inflammation: An Experimental Study Using both In Vivo and In Vitro Models.

Nutrients 2020 Jul 8;12(7). Epub 2020 Jul 8.

Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, UAE.

Nerolidol (NED) is a naturally occurring sesquiterpene alcohol present in various plants with potent anti-inflammatory effects. In the current study, we investigated NED as a putative anti-inflammatory compound in an experimental model of colonic inflammation. C57BL/6J male black mice (C57BL/6J) were administered 3% dextran sodium sulfate (DSS) in drinking water for 7 days to induce colitis. Six groups received either vehicle alone or DSS alone or DSS with oral NED (50, 100, and 150 mg/kg body weight/day by oral gavage) or DSS with sulfasalazine. Disease activity index (DAI), colonic histology, and biochemical parameters were measured. TNF-α-treated HT-29 cells were used as in vitro model of colonic inflammation to study NED (25 µM and 50 µM). NED significantly decreased the DAI and reduced the inflammation-associated changes in colon length as well as macroscopic and microscopic architecture of the colon. Changes in tissue Myeloperoxidase (MPO) concentrations, neutrophil and macrophage mRNA expression (CXCL2 and CCL2), and proinflammatory cytokine content (IL-1β, IL-6, and TNF-α) both at the protein and mRNA level were significantly reduced by NED. The increase in content of the proinflammatory enzymes, COX-2 and iNOS induced by DSS were also significantly inhibited by NED along with tissue nitrate levels. NED promoted Nrf2 nuclear translocation dose dependently. NED significantly increased antioxidant enzymes activity (Superoxide dismutase (SOD) and Catalase (CAT)), Hemeoxygenase-1 (HO-1), and SOD3 mRNA levels. NED treatment in TNF-α-challenged HT-29 cells significantly decreased proinflammatory chemokines (CXCL1, IL-8, CCL2) and COX-2 mRNA levels. NED supplementation attenuates colon inflammation through its potent antioxidant and anti-inflammatory activity both in in vivo and in vitro models of colonic inflammation.
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http://dx.doi.org/10.3390/nu12072032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400891PMC
July 2020

The Dual-Active Histamine H Receptor Antagonist and Acetylcholine Esterase Inhibitor E100 Alleviates Autistic-Like Behaviors and Oxidative Stress in Valproic Acid Induced Autism in Mice.

Int J Mol Sci 2020 Jun 3;21(11). Epub 2020 Jun 3.

Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 17666, UAE.

The histamine H3 receptor (H3R) functions as auto- and hetero-receptors, regulating the release of brain histamine (HA) and acetylcholine (ACh), respectively. The enzyme acetylcholine esterase (AChE) is involved in the metabolism of brain ACh. Both brain HA and ACh are implicated in several cognitive disorders like Alzheimer's disease, schizophrenia, anxiety, and narcolepsy, all of which are comorbid with autistic spectrum disorder (ASD). Therefore, the novel dual-active ligand E100 with high H3R antagonist affinity (hH3R: = 203 nM) and balanced AChE inhibitory effect (AChE: IC = 2 µM and BuChE: IC = 2 µM) was investigated on autistic-like sociability, repetitive/compulsive behaviour, anxiety, and oxidative stress in male C57BL/6 mice model of ASD induced by prenatal exposure to valproic acid (VPA, 500 mg/kg, intraperitoneal (i.p.)). Subchronic systemic administration with E100 (5, 10, and 15 mg/kg, i.p.) significantly and dose-dependently attenuated sociability deficits of autistic (VPA) mice in three-chamber behaviour (TCB) test (all < 0.05). Moreover, E100 significantly improved repetitive and compulsive behaviors by reducing the increased percentage of marbles buried in marble-burying behaviour (MBB) (all < 0.05). Furthermore, pre-treatment with E100 (10 and 15 mg/kg, i.p.) corrected decreased anxiety levels ( < 0.05), however, failed to restore hyperactivity observed in elevated plus maze (EPM) test. In addition, E100 (10 mg/kg, i.p.) mitigated oxidative stress status by increasing the levels of decreased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT), and decreasing the elevated levels of malondialdehyde (MDA) in the cerebellar tissues (all < 0.05). Additionally, E100 (10 mg/kg, i.p.) significantly reduced the elevated levels of AChE activity in VPA mice ( < 0.05). These results demonstrate the promising effects of E100 on in-vivo VPA-induced ASD-like features in mice, and provide evidence that a potent dual-active H3R antagonist and AChE inhibitor (AChEI) is a potential drug candidate for future therapeutic management of autistic-like behaviours.
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http://dx.doi.org/10.3390/ijms21113996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312782PMC
June 2020

Antagonism of Histamine H3 receptors Alleviates Pentylenetetrazole-Induced Kindling and Associated Memory Deficits by Mitigating Oxidative Stress, Central Neurotransmitters, and c-Fos Protein Expression in Rats.

Molecules 2020 Mar 30;25(7). Epub 2020 Mar 30.

Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, UAE.

Histamine H3 receptors (H3Rs) are involved in several neuropsychiatric diseases including epilepsy. Therefore, the effects of H3R antagonist E177 (5 and 10 mg/kg, intraperitoneal (i.p.)) were evaluated on the course of kindling development, kindling-induced memory deficit, oxidative stress levels (glutathione (GSH), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD)), various brain neurotransmitters (histamine (HA), acetylcholine (ACh), γ-aminobutyric acid (GABA)), and glutamate (GLU), acetylcholine esterase (AChE) activity, and c-Fos protein expression in pentylenetetrazole (PTZ, 40 mg/kg) kindled rats. E177 (5 and 10 mg/kg, i.p.) significantly decreased seizure score, increased step-through latency (STL) time in inhibitory avoidance paradigm, and decreased transfer latency time (TLT) in elevated plus maze (all < 0.05). Moreover, E177 mitigated oxidative stress by significantly increasing GSH, CAT, and SOD, and decreasing the abnormal level of MDA (all < 0.05). Furthermore, E177 attenuated elevated levels of hippocampal AChE, GLU, and c-Fos protein expression, whereas the decreased hippocampal levels of HA and ACh were modulated in PTZ-kindled animals (all < 0.05). The findings suggest the potential of H3R antagonist E177 as adjuvant to antiepileptic drugs with an added advantage of preventing cognitive impairment, highlighting the H3Rs as a potential target for the therapeutic management of epilepsy with accompanied memory deficits.
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http://dx.doi.org/10.3390/molecules25071575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181068PMC
March 2020

Experimental Models for the Discovery of Novel Anticonvulsant Drugs: Focus on Pentylenetetrazole-Induced Seizures and Associated Memory Deficits.

Curr Pharm Des 2020 ;26(15):1693-1711

Department of Pharmacology & Therapeutics, College of Medicine & Health Sciences, United Arab Emirates University, P.O. Box 17666 Al Ain, United States.

Epilepsy is a chronic neurological disorder characterized by irregular, excessive neuronal excitability, and recurrent seizures that affect millions of patients worldwide. Currently, accessible antiepileptic drugs (AEDs) do not adequately support all epilepsy patients, with around 30% patients not responding to the existing therapies. As lifelong epilepsy treatment is essential, the search for new and more effective AEDs with an enhanced safety profile is a significant therapeutic goal. Seizures are a combination of electrical and behavioral events that can induce biochemical, molecular, and anatomic changes. Therefore, appropriate animal models are required to evaluate novel potential AEDs. Among the large number of available animal models of seizures, the acute pentylenetetrazole (PTZ)-induced myoclonic seizure model is the most widely used model assessing the anticonvulsant effect of prospective AEDs, whereas chronic PTZ-kindled seizure models represent chronic models in which the repeated administration of PTZ at subconvulsive doses leads to the intensification of seizure activity or enhanced seizure susceptibility similar to that in human epilepsy. In this review, we summarized the memory deficits accompanying acute or chronic PTZ seizure models and how these deficits were evaluated applying several behavioral animal models. Furthermore, major advantages and limitations of the PTZ seizure models in the discovery of new AEDs were highlighted. With a focus on PTZ seizures, the major biochemicals, as well as morphological alterations and the modulated brain neurotransmitter levels associated with memory deficits have been illustrated. Moreover, numerous medicinal compounds with concurrent anticonvulsant, procognitive, antioxidant effects, modulating effects on several brain neurotransmitters in rodents, and several newly developed classes of compounds applying computer-aided drug design (CADD) have been under development as potential AEDs. The article details the in-silico approach following CADD, which can be utilized for generating libraries of novel compounds for AED discovery. Additionally, in vivo studies could be useful in demonstrating efficacy, safety, and novel mode of action of AEDs for further clinical development.
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http://dx.doi.org/10.2174/1381612826666200131105324DOI Listing
November 2020

The Neuroprotective Effects of Histamine H3 Receptor Antagonist E177 on Pilocarpine-Induced Status Epilepticus in Rats.

Molecules 2019 Nov 14;24(22). Epub 2019 Nov 14.

Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, UAE.

Epilepsy is a multifaceted neurological disorder which severely affects neuronal function. Some patients may experience status epilepticus (SE), a life-threatening state of ongoing seizure activity linked to cognitive dysfunction, necessitating an immediate intervention. The potential of histamine H3 receptors in several neuropsychiatric diseases including epilepsy is well recognized. In the current study, we aimed to explore the effect of H3R antagonist E177 on prevention and termination of pilocarpine (PLC)-induced SE in rats as well as evaluating the effects of E177 on the levels of oxidative stress in hippocampus tissues. The results showed that the survival rate of animals pretreated with E177 (5 and 10 mg/kg, intraperitoneal (i.p.)) was significantly increased during the first hour of observation, and animals were protected from SE incidence and showed a prolonged average of latency to the first seizure when compared with animals pretreated with PLC (400 mg/kg, i.p.). Moreover, the protective effect of E177 (10 mg/kg) on SE was partially reversed when rats were co- administered with H3R agonist -(α)-methylhistamine (RAM) and with the H2R antagonist zolantidine (ZOL), but not with the H1R antagonist pyrilamine (PYR). Furthermore, pretreatment with E177 (5 and 10 mg/kg) significantly decreased the abnormal levels of malondialdehyde (MDA), and increased levels of glutathione (GSH) in the hippocampal tissues of the treated rats. However, E177 failed to modulate the levels of catalase (CAT), superoxide dismutase (SOD), or acetylcholine esterase activity (AChE). Our findings suggest that the newly developed H3R antagonist E177 provides neuroprotection in a preclinical PLC-induced SE in rats, highlighting the histaminergic system as a potential therapeutic target for the therapeutic management of SE.
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http://dx.doi.org/10.3390/molecules24224106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891424PMC
November 2019

The dual-active histamine H3 receptor antagonist and acetylcholine esterase inhibitor E100 ameliorates stereotyped repetitive behavior and neuroinflammmation in sodium valproate induced autism in mice.

Chem Biol Interact 2019 Oct 30;312:108775. Epub 2019 Jul 30.

Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates. Electronic address:

Postnatal exposure to valproic acid (VPA) in rodents induces autism-like neurobehavioral defects which are comparable to the motor and cognitive deficits observed in humans with autism spectrum disorder (ASD). Histamine H3 receptor (H3R) and acetylcholine esterase (AChE) are involved in several cognitive disorders such as Alzheimer's disease, schizophrenia, anxiety, and narcolepsy, all of which are comorbid with ASD. Therefore, the present study aimed at evaluating effect of the novel dual-active ligand E100 with high H3R antagonist affinity and balanced AChE inhibition on autistic-like repetitive behavior, anxiety parameters, locomotor activity, and neuroinflammation in a mouse model of VPA-induced ASD in C57BL/6 mice. E100 (5, 10, and 15 mg/kg) dose-dependently and significantly ameliorated repetitive and compulsive behaviors by reducing the increased percentages of nestlets shredded (all P < 0.05). Moreover, pretreatment with E100 (10 and 15 mg/kg) attenuated disturbed anxiety levels (P < 0.05) but failed to restore the hyperactivity observed in the open field test. Furthermore, pretreatment with E100 (10 mg/kg) the increased microglial activation, proinflammatory cytokines and expression of NF-κB, iNOS, and COX-2 in the cerebellum as well as the hippocampus (all P < 0.05). These results demonstrate the ameliorative effects of E100 on repetitive compulsive behaviors in a mouse model of ASD. To our knowledge, this is the first in vivo demonstration of the effectiveness of a potent dual-active H3R antagonist and AChE inhibitor against autistic-like repetitive compulsive behaviors and neuroinflammation, and provides evidence for the role of such compounds in treating ASD.
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http://dx.doi.org/10.1016/j.cbi.2019.108775DOI Listing
October 2019

Lycopodium Attenuates Loss of Dopaminergic Neurons by Suppressing Oxidative Stress and Neuroinflammation in a Rat Model of Parkinson's Disease.

Molecules 2019 Jun 10;24(11). Epub 2019 Jun 10.

Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.

Parkinson's disease, a chronic, age related neurodegenerative disorder, is characterized by a progressive loss of nigrostriatal dopaminergic neurons. Several studies have proven that the activation of glial cells, presence of alpha-synuclein aggregates, and oxidative stress, fuels neurodegeneration, and currently there is no definitive treatment for PD. In this study, a rotenone-induced rat model of PD was used to understand the neuroprotective potential of Lycopodium (Lyc), a commonly-used potent herbal medicine. Immunohistochemcial data showed that rotenone injections significantly increased the loss of dopaminergic neurons in the substantia nigra, and decreased the striatal expression of tyrosine hydroxylase. Further, rotenone administration activated microglia and astroglia, which in turn upregulated the expression of α-synuclein, pro-inflammatory, and oxidative stress factors, resulting in PD pathology. However, rotenone-injected rats that were orally treated with lycopodium (50 mg/kg) were protected against dopaminergic neuronal loss by diminishing the expression of matrix metalloproteinase-3 (MMP-3) and MMP-9, as well as reduced activation of microglia and astrocytes. This neuroprotective mechanism not only involves reduction in pro-inflammatory response and α-synuclein expression, but also synergistically enhanced antioxidant defense system by virtue of the drug's multimodal action. These findings suggest that Lyc has the potential to be further developed as a therapeutic candidate for PD.
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http://dx.doi.org/10.3390/molecules24112182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600474PMC
June 2019

Pharmacological Properties, Molecular Mechanisms, and Pharmaceutical Development of Asiatic Acid: A Pentacyclic Triterpenoid of Therapeutic Promise.

Front Pharmacol 2018 4;9:892. Epub 2018 Sep 4.

Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.

Asiatic acid (AA) is a naturally occurring aglycone of ursane type pentacyclic triterpenoids. It is abundantly present in many edible and medicinal plants including that is a reputed herb in many traditional medicine formulations for wound healing and neuropsychiatric diseases. AA possesses numerous pharmacological activities such as antioxidant and anti-inflammatory and regulates apoptosis that attributes its therapeutic effects in numerous diseases. AA showed potent antihypertensive, nootropic, neuroprotective, cardioprotective, antimicrobial, and antitumor activities in preclinical studies. In various and studies, AA found to affect many enzymes, receptors, growth factors, transcription factors, apoptotic proteins, and cell signaling cascades. This review aims to represent the available reports on therapeutic potential and the underlying pharmacological and molecular mechanisms of AA. The review also also discusses the challenges and prospects on the pharmaceutical development of AA such as pharmacokinetics, physicochemical properties, analysis and structural modifications, and drug delivery. AA showed favorable pharmacokinetics and found bioavailable following oral or interaperitoneal administration. The studies demonstrate the polypharmacological properties, therapeutic potential and molecular mechanisms of AA in numerous diseases. Taken together the evidences from available studies, AA appears one of the important multitargeted polypharmacological agents of natural origin for further pharmaceutical development and clinical application. Provided the favorable pharmacokinetics, safety, and efficacy, AA can be a promising agent or adjuvant along with currently used modern medicines with a pharmacological basis of its use in therapeutics.
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http://dx.doi.org/10.3389/fphar.2018.00892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131672PMC
September 2018

The histamine H3R antagonist DL77 attenuates autistic behaviors in a prenatal valproic acid-induced mouse model of autism.

Sci Rep 2018 08 30;8(1):13077. Epub 2018 Aug 30.

Department of Pharmacology & Therapeutics, College of Medicine & Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, UAE.

Autistic spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment in social communication and restricted/repetitive behavior patterns or interests. Antagonists targeting histamine H3 receptor (H3R) are considered potential therapeutic agents for the therapeutic management of different brain disorders, e.g., cognitive impairments. Therefore, the effects of subchronic treatment with the potent and selective H3R antagonist DL77 (5, 10, or 15 mg/kg, i.p.) on sociability, social novelty, anxiety, and aggressive/repetitive behavior in male Tuck-Ordinary (TO) mice with ASD-like behaviors induced by prenatal exposure to valproic acid (VPA, 500 mg/kg, i.p.) were evaluated using the three-chamber test (TCT), marble burying test (MBT), nestlet shredding test (NST), and elevated plus maze (EPM) test. The results showed that VPA-exposed mice exhibited significantly lower sociability and social novelty preference compared to VPA-exposed mice that were pretreated with DL77 (10 or 15 mg/kg, i.p.). VPA-exposed mice presented a significantly higher percentage of buried marbles in MBT and shredded nestlet significantly more in NST compared to the control groups. However, VPA-exposed animals pretreated with DL77 (10 or 15 mg/kg, i.p.) buried a reduced percentage of marbles in MBT and presented a significantly lower percentage of shredding behavior in NST. On the other hand, pretreatment with DL77 (5, 10, or 15 mg/kg, i.p.) failed to restore the disturbed anxiety levels and hyperactivity observed in VPA-exposed animals in EPM, whereas the reference drug donepezil (DOZ, 1 mg/kg, i.p.) significantly palliated the anxiety and reduced the hyperactivity measures of VPA-exposed mice. Furthermore, pretreatment with DL77 (10 or 15 mg/kg, i.p.) modulated oxidative stress status by increasing GSH and decreasing MDA, and it attenuated the proinflammatory cytokines IL-1β, IL-6 and TNF-α exacerbated by lipopolysaccharide (LPS) challenge, in VPA-exposed mouse brain tissue. Taken together, these results provide evidence that modulation of brain histaminergic neurotransmission, such as by subchronic administration of the H3R antagonist DL77, may serve as an effective pharmacological therapeutic target to rescue ASD-like behaviors in VPA-exposed animals, although further investigations are necessary to corroborate and expand these initial data.
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http://dx.doi.org/10.1038/s41598-018-31385-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117350PMC
August 2018

Current Enlightenment About Etiology and Pharmacological Treatment of Autism Spectrum Disorder.

Front Neurosci 2018 16;12:304. Epub 2018 May 16.

Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.

Autistic Spectrum Disorder (ASD) is a complex neurodevelopmental brain disorder characterized by two core behavioral symptoms, namely impairments in social communication and restricted/repetitive behavior. The molecular mechanisms underlying ASD are not well understood. Recent genetic as well as non-genetic animal models contributed significantly in understanding the pathophysiology of ASD, as they establish autism-like behavior in mice and rats. Among the genetic causes, several chromosomal mutations including duplications or deletions could be possible causative factors of ASD. In addition, the biochemical basis suggests that several brain neurotransmitters, e.g., dopamine (DA), serotonin (5-HT), gamma-amino butyric acid (GABA), acetylcholine (ACh), glutamate (Glu) and histamine (HA) participate in the onset and progression of ASD. Despite of convincible understanding, risperidone and aripiprazole are the only two drugs available clinically for improving behavioral symptoms of ASD following approval by Food and Drug Administration (FDA). Till date, up to our knowledge there is no other drug approved for clinical usage specifically for ASD symptoms. However, many novel drug candidates and classes of compounds are underway for ASD at different phases of preclinical and clinical drug development. In this review, the diversity of numerous aetiological factors and the alterations in variety of neurotransmitter generation, release and function linked to ASD are discussed with focus on drugs currently used to manage neuropsychiatric symptoms related to ASD. The review also highlights the clinical development of drugs with emphasis on their pharmacological targets aiming at improving core symptoms in ASD.
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http://dx.doi.org/10.3389/fnins.2018.00304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964170PMC
May 2018

The Histamine H3 Receptor Antagonist DL77 Ameliorates MK801-Induced Memory Deficits in Rats.

Front Neurosci 2018 12;12:42. Epub 2018 Feb 12.

Department of Pharmacology & Therapeutics, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.

The role of Histamine H3 receptors (H3Rs) in memory, and the prospective of H3R antagonists in pharmacological control of neurodegenerative disorders, e.g., Alzheimer disease (AD) is well-accepted. For that reason, the procognitive effects of the H3R antagonist DL77 on cognitive impairments induced with MK801 were tested in an inhibitory passive avoidance paradigm (PAP) and novel object recognition (NOR) task in adult male rats, using donepezil (DOZ) as a standard drug. Acute systemic pretreatment with DL77 (2.5, 5, and 10 mg/kg, i.p.) significantly ameliorated memory deficits induced with MK801 in PAP (all < 0.05, = 7). The ameliorative effect of most promising dose of DL77 (5 mg/kg, i.p.) was reversed when rats were co-injected with the H3R agonist -(α)-methylhistamine (RAMH, 10 mg/kg, i.p.) ( = 0.701 for MK801-amnesic group vs. MK801+DL77+RAMH group, = 6). In the NOR paradigm, DL77 (5 mg/kg, i.p.) counteracted long-term memory (LTM) deficits induced with MK801 ( < 0.05, = 6-8), and the DL77-provided effect was similar to that of DOZ ( = 0.788, = 6-8), and was reversed when rats were co-injected with RAMH (10 mg/kg, i.p.) ( = 0.877, = 6, as compared to the (MK801)-amnesic group). However, DL77 (5 mg/kg, i.p.) did not alter short-term memory (STM) impairment in NOR test ( = 0.772, = 6-8, as compared to (MK801)-amnesic group). Moreover, DL77 (5 mg/kg) failed to modify anxiety and locomotor behaviors of animals innate to elevated-plus maze (EPM) ( = 0.67 for percentage of time spent exploring the open arms, = 0.52 for number of entries into the open arms, = 0.76 for percentage of entries into the open arms, and = 0.73 number of closed arm entries as compared to saline-treated groups, all = 6), demonstrating that the procognitive effects observed in PAP or NOR tests were unconnected to alterations in emotions or in natural locomotion of tested animals. These results signify the potential involvement of H3Rs in modulating neurotransmitters related to neurodegenerative disorders, e.g., AD.
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http://dx.doi.org/10.3389/fnins.2018.00042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5816071PMC
February 2018

Therapeutic Potential and Pharmaceutical Development of Thymoquinone: A Multitargeted Molecule of Natural Origin.

Front Pharmacol 2017 21;8:656. Epub 2017 Sep 21.

Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates UniversityAl Ain, United Arab Emirates.

Thymoquinone, a monoterpene molecule is chemically known as 2-methyl-5-isopropyl-1, 4-benzoquinone. It is abundantly present in seeds of L. that is popularly known as black cumin or black seed and belongs to the family . A large number of studies have revealed that thymoquinone is the major active constituent in oil this constituent is responsible for the majority of the pharmacological properties. The beneficial organoprotective activities of thymoquinone in experimental animal models of different human diseases are attributed to the potent anti-oxidant and anti-inflammatory properties. Thymoquinone has also been shown to alter numerous molecular and signaling pathways in many inflammatory and degenerative diseases including cancer. Thymoquinone has been reported to possess potent lipophilicity and limited bioavailability and exhibits light and heat sensitivity. Altogether, these physiochemical properties encumber the successful formulation for the delivery of drug in oral dosages form and restrict the pharmaceutical development. In recent past, many efforts were undertaken to improve the bioavailability for clinical usage by manipulating the physiochemical parameters. The present review aimed to provide insights regarding the physicochemical characteristics, pharmacokinetics and the methods to promote pharmaceutical development and endorse the clinical usage of TQ in future by overcoming the associated physiochemical obstacles. It also enumerates briefly the pharmacological and molecular targets of thymoquinone as well as the pharmacological properties in various diseases and the underlying molecular mechanism. Though, a convincing number of experimental studies are available but human studies are not available with thymoquinone despite of the long history of use of black cumin in different diseases. Thus, the clinical studies including pharmacokinetic studies and regulatory toxicity studies are required to encourage the clinical development of thymoquinone.
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http://dx.doi.org/10.3389/fphar.2017.00656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5613109PMC
September 2017

Pharmacological Properties and Molecular Mechanisms of Thymol: Prospects for Its Therapeutic Potential and Pharmaceutical Development.

Front Pharmacol 2017 26;8:380. Epub 2017 Jun 26.

Department of Pharmacology and Therapeutics, College of Medicine and Health Science, United Arab Emirates UniversityAl Ain, United Arab Emirates.

Thymol, chemically known as 2-isopropyl-5-methylphenol is a colorless crystalline monoterpene phenol. It is one of the most important dietary constituents in thyme species. For centuries, it has been used in traditional medicine and has been shown to possess various pharmacological properties including antioxidant, free radical scavenging, anti-inflammatory, analgesic, antispasmodic, antibacterial, antifungal, antiseptic and antitumor activities. The present article presents a detailed review of the scientific literature which reveals the pharmacological properties of thymol and its multiple therapeutic actions against various cardiovascular, neurological, rheumatological, gastrointestinal, metabolic and malignant diseases at both biochemical and molecular levels. The noteworthy effects of thymol are largely attributed to its anti-inflammatory ( inhibiting recruitment of cytokines and chemokines), antioxidant ( scavenging of free radicals, enhancing the endogenous enzymatic and non-enzymatic antioxidants and chelation of metal ions), antihyperlipidemic ( increasing the levels of high density lipoprotein cholesterol and decreasing the levels of low density lipoprotein cholesterol and low density lipoprotein cholesterol in the circulation and membrane stabilization) ( maintaining ionic homeostasis) effects. This review presents an overview of the current and data supporting thymol's therapeutic activity and the challenges concerning its use for prevention and its therapeutic value as a dietary supplement or as a pharmacological agent or as an adjuvant along with current therapeutic agents for the treatment of various diseases. It is one of the potential candidates of natural origin that has shown promising therapeutic potential, pharmacological properties and molecular mechanisms as well as pharmacokinetic properties for the pharmaceutical development of thymol.
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http://dx.doi.org/10.3389/fphar.2017.00380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5483461PMC
June 2017

Therapeutic Potential and Molecular Mechanisms of Gaertn in Countering Nephrotoxicity in Rats Induced by the Chemotherapeutic Agent Cisplatin.

Front Pharmacol 2016 3;7:350. Epub 2016 Oct 3.

Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University Al Ain, UAE.

Gaertn. belonging to family Euphorbiaceae is commonly known as Indian gooseberry or "Amla" in India. It is used as a 'rejuvenating herb' in traditional system of Indian medicine. It has been shown to possess antioxidant, anti-inflammatory and anti-apoptotic effects. Thus, on the basis of its biological effects, the present study was undertaken to evaluate the protective effect of the dried fruit extract of the (EO) in cisplatin-induced nephrotoxicity in rats and also to evaluate the mechanism of its nephroprotection. The study was done on male albino Wistar rats. They were divided into six groups ( = 6) viz. control, cisplatin-control, cisplatin and EO (150, 300, and 600 mg/kg; p.o. respectively in different groups) and EO only (600 mg/kg; p.o. only). EO was administered orally to the rats for a period of 10 days and on the 7th day, a single injection of cisplatin (8 mg/kg; i.p.) was administered to the cisplatin-control and EO treatment groups. The rats were sacrificed on the 10th day. Cisplatin-control rats had deranged renal function parameters and the kidney histology confirmed the presence of acute tubular necrosis. Furthermore, there were increased oxidative stress, apoptosis and inflammation along with higher expression of MAPK pathway proteins in the rat kidney from the cisplatin-control group. Contrary to this, EO (600 mg/kg) significantly normalized renal function, bolstered antioxidant status and ameliorated histological alterations. The inflammation and apoptosis were markedly lower in comparison to cisplatin-control rats. Furthermore, EO (600 mg/kg) inhibited MAPK phosphorylation which was instrumental in preserving renal function and morphology. In conclusion, the results of our study demonstrated that EO attenuated cisplatin-induced nephrotoxicity in rats through suppression of MAPK induced inflammation and apoptosis.
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http://dx.doi.org/10.3389/fphar.2016.00350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045924PMC
October 2016

Cannabinoid Type 2 (CB2) Receptors Activation Protects against Oxidative Stress and Neuroinflammation Associated Dopaminergic Neurodegeneration in Rotenone Model of Parkinson's Disease.

Front Neurosci 2016 2;10:321. Epub 2016 Aug 2.

Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University Al Ain, UAE.

The cannabinoid type two receptors (CB2), an important component of the endocannabinoid system, have recently emerged as neuromodulators and therapeutic targets for neurodegenerative diseases including Parkinson's disease (PD). The downregulation of CB2 receptors has been reported in the brains of PD patients. Therefore, both the activation and the upregulation of the CB2 receptors are believed to protect against the neurodegenerative changes in PD. In the present study, we investigated the CB2 receptor-mediated neuroprotective effect of β-caryophyllene (BCP), a naturally occurring CB2 receptor agonist, in, a clinically relevant, rotenone (ROT)-induced animal model of PD. ROT (2.5 mg/kg BW) was injected intraperitoneally (i.p.) once daily for 4 weeks to induce PD in male Wistar rats. ROT injections induced a significant loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and DA striatal fibers, following activation of glial cells (astrocytes and microglia). ROT also caused oxidative injury evidenced by the loss of antioxidant enzymes and increased nitrite levels, and induction of proinflammatory cytokines: IL-1β, IL-6 and TNF-α, as well as inflammatory mediators: NF-κB, COX-2, and iNOS. However, treatment with BCP attenuated induction of proinflammatory cytokines and inflammatory mediators in ROT-challenged rats. BCP supplementation also prevented depletion of glutathione concomitant to reduced lipid peroxidation and augmentation of antioxidant enzymes: SOD and catalase. The results were further supported by tyrosine hydroxylase immunohistochemistry, which illustrated the rescue of the DA neurons and fibers subsequent to reduced activation of glial cells. Interestingly, BCP supplementation demonstrated the potent therapeutic effects against ROT-induced neurodegeneration, which was evidenced by BCP-mediated CB2 receptor activation and the fact that, prior administration of the CB2 receptor antagonist AM630 diminished the beneficial effects of BCP. The present study suggests that BCP has the potential therapeutic efficacy to elicit significant neuroprotection by its anti-inflammatory and antioxidant activities mediated by activation of the CB2 receptors.
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http://dx.doi.org/10.3389/fnins.2016.00321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4969295PMC
August 2016

Cardiovascular friendly natural products: a promising approach in the management of CVD.

Nat Prod Res 2010 May;24(9):873-98

Department of Biochemistry, University College of Medical Sciences, University of Delhi, Delhi, India.

Natural products play an important role as nutritional supplements and provide potential health benefits in cardiovascular diseases (CVD). Compiling data from experimental, epidemiological and clinical studies indicates that dietary nutrients have profound cardioprotective effects in the primary as well as secondary prevention of coronary heart disease, hence they are considered as cardiovascular friendly natural products. The mechanism of cardioprotection produced by dietary nutritional supplements such as flavonoids (citrus fruits, pulses, red wine, tea and cocoa), olive oil, omega-3 (omega-3) fatty acids (fish oil and fish-based products), lycopene (tomato and tomato-based products), resveratrol (grapes and red wine), coffee, and soy in the prevention and treatment of cardiovascular disorders have been discussed in the present review, with the emphasis of epidemiological and clinical studies. Based on the intriguing results of various studies, prophylactic and therapeutic potential of cardiovascular friendly natural products have been suggested. The supplementation of cardiovascular friendly natural products needs to be considered in all populations who have high prevalence of CVD.
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http://dx.doi.org/10.1080/14786410903417378DOI Listing
May 2010

Effect of Commiphora mukul extract on cardiac dysfunction and ventricular function in isoproterenol-induced myocardial infarction.

Indian J Exp Biol 2008 Sep;46(9):646-52

Cardiovascular Laboratory, Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110 029, India.

In present study, hydroalcoholic extract of C. mukul significantly improved the cardiac function and prevented myocardial ischemic impairment manifested in the form of increased heart rate, decreased arterial pressure, increased left ventricular end diastolic pressure, and altered myocardial contractility indices. C. mukul treatment additionally also produced a significant increase in lactate dehydrogenase levels and prevented decline of protein content in heart. C. mukul preserved the structural integrity of myocardium. Reduced leakage of myocyte enzyme lactate dehydrogenase and maintenance of structural integrity of myocardium along with favorable modulation of cardiac function and improved cardiac performance indicate the salvage of myocardium with C. mukul treatment. Guggulsterones which are considered to be responsible for most of the therapeutic properties of C. mukul may underlie the observed cardioprotective effect of C. mukul against cardiac dysfunction in isoproterenol-induced ischemic rats.
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September 2008