Publications by authors named "Manoj Govindarajulu"

19 Publications

  • Page 1 of 1

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

Heliyon 2021 Apr 13;7(4):e06730. Epub 2021 Apr 13.

Department of Drug Discovery and Development, Auburn University, Auburn, AL, USA.

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.
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http://dx.doi.org/10.1016/j.heliyon.2021.e06730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066425PMC
April 2021

The Cardioprotective Mechanism of Phenylaminoethyl Selenides (PAESe) Against Doxorubicin-Induced Cardiotoxicity Involves Frataxin.

Front Pharmacol 2020 12;11:574656. Epub 2021 Apr 12.

Department of Drug, Discovery and Development, Harrison School of Pharmacy, Auburn University, Alabama, AL, United States.

Doxorubicin (DOX) is an anthracycline cancer chemotherapeutic that exhibits cumulative dose-limiting cardiotoxicity and limits its clinical utility. DOX treatment results in the development of morbid cardiac hypertrophy that progresses to congestive heart failure and death. Recent evidence suggests that during the development of DOX mediated cardiac hypertrophy, mitochondrial energetics are severely compromised, thus priming the cardiomyocyte for failure. To mitigate cumulative dose (5 mg/kg, QIW x 4 weeks with 2 weeks recovery) dependent DOX, mediated cardiac hypertrophy, we applied an orally active selenium based compound termed phenylaminoethyl selenides (PAESe) (QIW 10 mg/kg x 5) to our animal model and observed that PAESe attenuates DOX-mediated cardiac hypertrophy in athymic mice, as observed by MRI analysis. Mechanistically, we demonstrated that DOX impedes the stability of the iron-sulfur cluster biogenesis protein Frataxin (FXN) (0.5 fold), resulting in enhanced mitochondrial free iron accumulation (2.5 fold) and reduced aconitase activity (0.4 fold). Our findings further indicate that PAESe prevented the reduction of FXN levels and the ensuing elevation of mitochondrial free iron levels. PAESe has been shown to have anti-oxidative properties in part, by regeneration of glutathione levels. Therefore, we observed that PAESe can mitigate DOX mediated cardiac hypertrophy by enhancing glutathione activity (0.4 fold) and inhibiting ROS formation (1.8 fold). Lastly, we observed that DOX significantly reduced cellular respiration (basal (5%) and uncoupled (10%)) in H9C2 cardiomyoblasts and that PAESe protects against the DOX-mediated attenuation of cellular respiration. In conclusion, the current study determined the protective mechanism of PAESe against DOX mediated myocardial damage and that FXN is implicitly involved in DOX-mediated cardiotoxicity.
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http://dx.doi.org/10.3389/fphar.2020.574656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072348PMC
April 2021

Nutraceutical based SIRT3 activators as therapeutic targets in Alzheimer's disease.

Neurochem Int 2021 03 12;144:104958. Epub 2021 Jan 12.

Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL 36849, USA. Electronic address:

Alzheimer's disease (AD) is the most common neurodegenerative disease, and its incidence is increasing worldwide with increased lifespan. Currently, there is no effective treatment to cure or prevent the progression of AD, which indicates the need to develop novel therapeutic targets and agents. Sirtuins, especially SIRT3, a mitochondrial deacetylase, are NAD-dependent histone deacetylases involved in aging and longevity. Accumulating evidence indicates that SIRT3 dysfunction is strongly associated with pathologies of AD, hence, therapeutic modulation of SIRT3 activity may be a novel application to ameliorate the pathologies of AD. Natural products commonly used in traditional medicine have wide utility and appear to have therapeutic benefits for the treatment of neurodegenerative diseases such as AD. The present review summarizes the currently available natural SIRT3 activators and their potentially neuroprotective molecular mechanisms of action that make them a promising agent in the treatment and management of neurodegenerative diseases such as AD.
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http://dx.doi.org/10.1016/j.neuint.2021.104958DOI Listing
March 2021

Enhanced Bioavailability of Boswellic Acid by : A Computational and Pharmacokinetic Study.

Front Pharmacol 2020 15;11:551911. Epub 2020 Dec 15.

Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, United States.

Chronic inflammation is a key culprit factor in the onset and progression of several diseases. Novel and pharmacologically effective therapeutic approaches are needed for new treatment remedy or improved pharmacokinetics and pharmacodynamics for existing synthetic drugs, in particular natural products. Boswellic acids are well-known natural products, with capacity to effectively retard inflammation without severe adverse effects. However, the therapeutic use of Boswellic acids are greatly hindered by its poor pharmacokinetic properties. Co-administration strategies that facilitate the oral absorption and distribution of Boswellic acids should lead to a safe and more effective use of this product prophylactically and therapeutically in inflammatory disorders. In this study, we examined the effect of extract on the absorption and bioavailability of Boswellic acid in rabbits. In addition, we further explored computational pharmacodynamic interactions between and Boswellic acid. extract at 2.5 and 10 mg/kg, increased the bioavailability of Boswellic acid ( < 0.05). Based on our drug-based computational modeling, cytochrome P450 (CYP450)-mediated mechanism was involved in increased bioavailability. These findings confirmed that with Boswellic acid may be administered orally together for effective therapeutic efficacy. Thus, our studies support the application of with Boswellic acid as a novel therapeutic avenue in diseases associated with inflammation.
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http://dx.doi.org/10.3389/fphar.2020.551911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770183PMC
December 2020

Drug Discovery and Development of Novel Therapeutics for Inhibiting TMAO in Models of Atherosclerosis and Diabetes.

Front Physiol 2020 29;11:567899. Epub 2020 Oct 29.

Drug Discovery and Development, Auburn University, Auburn, AL, United States.

Diabetes mellitus exists as a comorbidity with congestive heart failure (CHF). However, the exact molecular signaling mechanism linking CHF as the major form of mortality from diabetes remains unknown. Type 2 diabetic patients display abnormally high levels of metabolic products associated with gut dysbiosis. One such metabolite, trimethylamine N-oxide (TMAO), has been observed to be directly related with increased incidence of cardiovascular diseases (CVD) in human patients. TMAO a gut-liver metabolite, comes from the metabolic degenerative product trimethylamine (TMA) that is produced from gut microbial metabolism. Elevated levels of TMAO in diabetics and obese patients are observed to have a direct correlation with increased risk for major adverse cardiovascular events. The pro-atherogenic effect of TMAO is attributed to enhancing inflammatory pathways with cholesterol and bile acid dysregulation, promoting foam cell formation. Recent studies have revealed several potential therapeutic strategies for reducing TMAO levels and will be the central focus for the current review. However, few have focused on developing rational drug therapeutics and may be due to the gaps in knowledge for understanding the mechanism by which microbial TMA producing enzymes and hepatic flavin-containing monoxygenase (FMO) can work together in preventing elevation of TMAO levels. Therefore, it is critical to understand the advantages of developing a novel rational drug design strategy that manipulates FMO production of TMAO and TMA production by microbial enzymes. This review will focus on the inspection of FMO manipulation, as well as gut microbiota dysbiosis and its influence on metabolic disorders including cardiovascular disease and describe novel potential pharmacological therapeutic development.
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http://dx.doi.org/10.3389/fphys.2020.567899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658318PMC
October 2020

Application of Extrusion-Based 3D Printed Dosage Forms in the Treatment of Chronic Diseases.

J Pharm Sci 2020 12 6;109(12):3551-3568. Epub 2020 Oct 6.

Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL 36849, USA. Electronic address:

Chronic disease management has been a significant burden in many countries. As most treatment options involve long-term pharmacotherapy, patient compliance has been a challenge, as patients have to remember taking medications on time at the prescribed dose for each disease state. Patients are often required to split the dosage unit, which may lead to under- or over-dose and dose-related adverse effects. However, 3D printing technologies have been used for fabricating personalized medications and multiple drugs in a single dose unit (polypills), which might greatly reduce treatment monitoring, dosing errors, and follow-ups with the health care providers. Extrusion-based 3D printing is the most used technology to fabricate polypills and to customize the dose, dosage form, and release kinetics, which might potentially reduce the risk of patient non-compliance. Although extrusion-based 3D printing has existed for some time, interest in its potential to fabricate dosage forms for treating chronic diseases is still in its infancy. This review focuses on the various extrusion-based 3D printing technologies such as fused deposition modeling, pressure-assisted microsyringe, and direct powder extrusion 3D printing in the preparation of customizable, multi-drug dosage forms for treating chronic diseases.
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http://dx.doi.org/10.1016/j.xphs.2020.09.042DOI Listing
December 2020

Gut Metabolite TMAO Induces Synaptic Plasticity Deficits by Promoting Endoplasmic Reticulum Stress.

Front Mol Neurosci 2020 12;13:138. Epub 2020 Aug 12.

Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, United States.

Dysbiosis of gut microbiota is strongly associated with metabolic diseases including diabetes mellitus, obesity, and cardiovascular disease. Recent studies indicate that Trimethylamine N-oxide (TMAO), a gut microbe-dependent metabolite is implicated in the development of age-related cognitive decline. However, the mechanisms of the impact of TMAO on neuronal function has not been elucidated. In the current study, we investigated the relationship between TMAO and deficits in synaptic plasticity in an Alzheimer's model (3×Tg-AD) and insulin resistance (Leptin deficient db/db) mouse by measuring plasma and brain levels of TMAO. We observed increased TMAO levels in the plasma and brain of both db/db and 3×Tg-AD mice in comparison to wild-type mice. Besides, TMAO levels further increased as mice progressed in age. Deficits in synaptic plasticity, in the form of reduced long-term potentiation (LTP), were noted in both groups of mice in comparison to wild-type mice. To further explore the impact of TMAO on neuronal function, we utilized an model by incubating wild-type hippocampal brain slices with TMAO and found impaired synaptic transmission. We observed that TMAO induced the PERK-EIF2α-ER stress signaling axis in TMAO treated slices as well as in both db/db and 3×Tg-AD mice. Lastly, we also observed altered presynaptic and reduced postsynaptic receptor expression. Our findings suggest that TMAO may induce deficits in synaptic plasticity through the ER stress-mediated PERK signaling pathway. Our results offer novel insight into the mechanism by which TMAO may induce cognitive deficits by promoting ER stress and identifies potential targets for therapeutic intervention.
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http://dx.doi.org/10.3389/fnmol.2020.00138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437142PMC
August 2020

Augmented oxidative stress and reduced mitochondrial function in ageing goat testis.

Vet Med Sci 2020 11 6;6(4):766-774. Epub 2020 Jul 6.

Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.

Recently, there is a significant increase in the commercial use of goat products. Nevertheless, there are very few reports on the characterization of redox biomarkers and mitochondrial function in the goat testis. Therefore, in this study we studied the markers of oxidative stress and mitochondrial functions in the goat testis during the process of ageing. Alterations in the markers of oxidative stress/redox biomarkers (contents of reactive oxygen species, nitrite, lipid peroxide, protein carbonyl, glutathione and activities of glutathione peroxidase, monoamine oxidase) and mitochondrial function (Complex-I and Complex-IV activities) were elucidated during the process of ageing. Augmented oxidative stress and decreased mitochondrial function were prominent during ageing in the goat testis. Ageing can lead to induction of oxidative stress and decreased production of ATP; however, the prooxidants generated must be effectively removed from the body by the innate antioxidant defence system to minimize the damage to the host tissue. Conversely, the antioxidants cannot completely scavenge the excessive amount of reactive oxygen species produced during ageing or pathological conditions leading to significant cell death and tissue damage. Thus, the use of effective and potent antioxidants in the feed could significantly reduce oxidative stress and improve mitochondrial function, resulting in enriched goat health.
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http://dx.doi.org/10.1002/vms3.296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738717PMC
November 2020

Elucidating the anti-melanoma effect and mechanisms of Hispolon.

Life Sci 2020 Sep 6;256:117702. Epub 2020 May 6.

Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL 36849. Electronic address:

There is a rapid increase in the incidence of melanoma which has led to a global crisis. Thus, there is a great need for developing novel, safe and effective drugs for the treatment of melanoma. Hispolon is a small molecular weight polyphenol derived from Phellinus linteus, which has antioxidant, anti-inflammatory and anti-proliferative activities. Hispolon has been reported to induce apoptosis in gastric cancer, hepatocellular carcinoma, and myeloid leukemia. However, the anticancer effect in melanoma is not well elucidated. Thus, our present study was to investigate the anti-cancer effect of hispolon on melanoma cancer cells. B16BL6 cells were treated with different concentrations of hispolon for 24 h and the effect on oxidative stress, mitochondrial functions, apoptosis and cell proliferation were studied. Hispolon is a potent generator of reactive oxygen species, nitrite and lipid peroxide levels. Furthermore, it significantly inhibits the expression of Bcl-2 and promotes the expression of Bax, increases the activity of caspase 1 and 3, inhibits mitochondrial Complex I and IV activities. By the above mechanisms, hispolon dose-dependently exhibited the antimelanoma effect similar to the well established pharmacological agent, curcumin. Thus, hispolon can be a potent anti-melanoma drug in the future if the pharmacodynamic effects and the toxicological studies are appropriately carried out.
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http://dx.doi.org/10.1016/j.lfs.2020.117702DOI Listing
September 2020

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

Toxicol Mech Methods 2020 Jul 14;30(6):454-461. Epub 2020 May 14.

Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.

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.
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http://dx.doi.org/10.1080/15376516.2020.1760984DOI Listing
July 2020

Adiponectin Knockout Mice Display Cognitive and Synaptic Deficits.

Front Endocrinol (Lausanne) 2019 22;10:819. Epub 2019 Nov 22.

Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, United States.

Adiponectin is an adipokine that has recently been under investigation for potential neuroprotective effects in various brain disorders including Alzheimer's disease, stroke, and depression. Adiponectin receptors (AdipoR1 and AdipoR2) are found throughout various brain regions, including the hippocampus. However, the role of these receptors in synaptic and cognitive function is not clear. Therefore, the goal of the current study was to evaluate synaptic and cognitive function in the absence of adiponectin. The current study utilized 12-month-old adiponectin knockout (APN-KO) mice and age-matched controls to study cognitive and hippocampal synaptic alterations. We determined that AdipoR1 and AdipoR2 are present in the synaptosome, with AdipoR2 displaying increased presynaptic vs. postsynaptic localization, whereas AdipoR1 was enriched in both the presynaptic and postsynaptic fractions. APN-KO mice displayed cognitive deficits in the novel object recognition (NOR) and Y-maze tests. This was mirrored by deficits in long-term potentiation (LTP) of the hippocampal Schaefer collateral pathway in APN-KO mice. APN-KO mice also displayed a reduction in basal synaptic transmission and an increase in presynaptic release probability. Deficits in LTP were rescued through hippocampal slice incubation with the adiponectin receptor agonist, AdipoRon, indicating that acute alterations in adiponectin receptor signaling influence synaptic function. Along with the deficits in LTP, altered levels of key presynaptic and postsynaptic proteins involved in glutamatergic neurotransmission were observed in APN-KO mice. Taken together, these results indicate that adiponectin is an important regulator of cognition and synaptic function in the hippocampus. Future studies should examine the role of specific adiponectin receptors in synaptic processes.
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http://dx.doi.org/10.3389/fendo.2019.00819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886372PMC
November 2019

Immunomodulatory actions of a Polynesian herb Noni (Morinda citrifolia) and its clinical applications.

Complement Ther Med 2019 Dec 3;47:102206. Epub 2019 Oct 3.

Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, 36849, USA. Electronic address:

Morinda citrifolia (Noni) is a popular traditional medicinal plant consumed in various forms in several countries around the world as a complementary and alternative treatment due to its established health benefits. Noni is rich in bioactive substances and has significantly exhibited pro-oxidant and immunomodulatory effects. In this review, we highlight the pharmacological basis related to the phytochemicals and polysaccharides present in Noni and its potential therapeutic effects. We screened electronic databases such as PubMed, Google Scholar, Scopus for scientific literature. Our results indicate that Noni is beneficial for various diseases with its crude extracts showing therapeutic benefit for a wide range of pathological diseases. We believe that further pharmacological and toxicological studies in addition to well-designed controlled clinical trials can validate Noni to be an effective and novel natural product for prophylactic and therapeutic use of several diseases.
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http://dx.doi.org/10.1016/j.ctim.2019.102206DOI Listing
December 2019

Early postoperative outcomes of pterygium surgery: Sutures versus autogenous serum in-situ fixation of limbal conjunctival autograft.

Life Sci 2019 Mar 10;221:93-98. Epub 2019 Feb 10.

Department of Ophthalmology, J.J.M. Medical College, Davangere 577004, Karnataka, India.

Limbal Conjunctival Autograft Transplantation (LCAT) is considered to be the most effective treatment option for pterygium with the least recurrence rate and rapid restoration of normal epithelial morphology. Of the many available methods for securing Limbal Conjunctival Autograft (LCAG), sutures and autogenous serum in-situ are cost-effective and offers better outcomes.

Aim: To compare the outcome of surgeries between the two groups: Group I - LCAG secured with autogenous serum in-situ versus Group II - LCAG secured with sutures.

Main Methods: A prospective randomized control trial conducted on 60 patients who were equally divided into two groups. Post-operative follow-up visits were scheduled at 1st week, 3rd week and 6th week. They were examined for pain, foreign body sensation, subconjunctival hemorrhage, tearing, hyperemia, graft edema, graft displacement, graft retraction, recurrence and/or any other complications and were graded depending on the severity. Mean surgical time was compared between the two groups.

Key Findings: Average duration of surgery was significantly less in Group I than in Group II. Postoperatively, symptoms like pain, foreign body sensation, tearing and hyperemia were less common in Group I, furthermore subconjunctival hemorrhage and graft edema were more in Group II.

Significance: Though both the procedures are safe and effective, the use of autogenous serum in-situ significantly shortens the duration of surgery and is accompanied by lesser postoperative discomfort and inflammation. However, long-term studies are needed to assess the risk of recurrence. Graft displacement remains a severe, but infrequent complication.
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http://dx.doi.org/10.1016/j.lfs.2019.02.019DOI Listing
March 2019

Signaling Mechanisms of Selective PPAR Modulators in Alzheimer's Disease.

PPAR Res 2018 21;2018:2010675. Epub 2018 Oct 21.

Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by abnormal protein accumulation, synaptic dysfunction, and cognitive impairment. The continuous increase in the incidence of AD with the aged population and mortality rate indicates the urgent need for establishing novel molecular targets for therapeutic potential. Peroxisome proliferator-activated receptor gamma (PPAR) agonists such as rosiglitazone and pioglitazone reduce amyloid and tau pathologies, inhibit neuroinflammation, and improve memory impairments in several rodent models and in humans with mild-to-moderate AD. However, these agonists display poor blood brain barrier permeability resulting in inadequate bioavailability in the brain and thus requiring high dosing with chronic time frames. Furthermore, these dosing levels are associated with several adverse effects including increased incidence of weight gain, liver abnormalities, and heart failure. Therefore, there is a need for identifying novel compounds which target PPAR more selectively in the brain and could provide therapeutic benefits without a high incidence of adverse effects. This review focuses on how PPAR agonists influence various pathologies in AD with emphasis on development of novel selective PPAR modulators.
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http://dx.doi.org/10.1155/2018/2010675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215547PMC
October 2018

Role of Adiponectin in Central Nervous System Disorders.

Neural Plast 2018 29;2018:4593530. Epub 2018 Jul 29.

Department of Drug Discovery and Development, Auburn University, Auburn, AL, USA.

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.
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http://dx.doi.org/10.1155/2018/4593530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087588PMC
November 2018

Autotaxin⁻Lysophosphatidic Acid Signaling in Alzheimer's Disease.

Int J Mol Sci 2018 06 21;19(7). Epub 2018 Jun 21.

Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA.

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.
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http://dx.doi.org/10.3390/ijms19071827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073975PMC
June 2018

SIRT3 activator Honokiol attenuates β-Amyloid by modulating amyloidogenic pathway.

PLoS One 2018 11;13(1):e0190350. Epub 2018 Jan 11.

Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, United States of America.

Honokiol (poly-phenolic lignan from Magnolia grandiflora) is a Sirtuin-3 (SIRT3) activator which exhibit antioxidant activity and augment mitochondrial functions in several experimental models. Modern evidence suggests the critical role of SIRT3 in the progression of several metabolic and neurodegenerative diseases. Amyloid beta (Aβ), the precursor to extracellular senile plaques, accumulates in the brains of patients with Alzheimer's disease (AD) and is related to the development of cognitive impairment and neuronal cell death. Aβ is generated from amyloid-β precursor protein (APP) through sequential cleavages, first by β-secretase and then by γ-secretase. Drugs modulating this pathway are believed to be one of the most promising strategies for AD treatment. In the present study, we found that Honokiol significantly enhanced SIRT3 expression, reduced reactive oxygen species generation and lipid peroxidation, enhanced antioxidant activities, and mitochondrial function thereby reducing Aβ and sAPPβ levels in Chinese Hamster Ovarian (CHO) cells (carrying the amyloid precursor protein-APP and Presenilin PS1 mutation). Mechanistic studies revealed that Honokiol affects neither protein levels of APP nor α-secretase activity. In contrast, Honokiol increased the expression of AMPK, CREB, and PGC-1α, thereby inhibiting β-secretase activity leading to reduced Aβ levels. These results suggest that Honokiol is an activator of SIRT3 capable of improving antioxidant activity, mitochondrial energy regulation, while decreasing Aβ, thereby indicating it to be a lead compound for AD drug development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0190350PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764272PMC
February 2018

Assessment of the cerebellar neurotoxic effects of nicotine in prenatal alcohol exposure in rats.

Life Sci 2018 Feb 7;194:177-184. Epub 2017 Dec 7.

Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, USA. Electronic address:

The adverse effects of prenatal nicotine and alcohol exposure on human reproductive outcomes are a major scientific and public health concern. In the United States, substantial percentage of women (20-25%) of childbearing age currently smoke cigarettes and consume alcohol, and only a small percentage of these individuals quit after learning of their pregnancy. However, there are very few scientific reports on the effect of nicotine in prenatal alcohol exposure on the cerebellum of the offspring. Therefore, this study was conducted to investigate the cerebellar neurotoxic effects of nicotine in a rodent model of Fetal Alcohol Spectrum Disorder (FASD). In this study, we evaluated the behavioral changes, biochemical markers of oxidative stress and apoptosis, mitochondrial functions and the molecular mechanisms associated with nicotine in prenatal alcohol exposure on the cerebellum. Prenatal nicotine and alcohol exposure induced oxidative stress, did not affect the mitochondrial functions, increased the monoamine oxidase activity, increased caspase expression and decreased ILK, PSD-95 and GLUR1 expression without affecting the GSK-3β. Thus, our current study of prenatal alcohol and nicotine exposure on cerebellar neurotoxicity may lead to new scientific perceptions and novel and suitable therapeutic actions in the future.
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http://dx.doi.org/10.1016/j.lfs.2017.12.010DOI Listing
February 2018

Comparing the dopaminergic neurotoxic effects of benzylpiperazine and benzoylpiperazine.

Toxicol Mech Methods 2018 Mar 28;28(3):177-186. Epub 2017 Sep 28.

a Department of Drug Discovery and Development , Harrison School of Pharmacy, Auburn University , Auburn , AL , USA.

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.
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http://dx.doi.org/10.1080/15376516.2017.1376024DOI Listing
March 2018