Publications by authors named "Muralikrishnan Dhanasekaran"

70 Publications

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

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

Co-Delivery of Hispolon and Doxorubicin Liposomes Improves Efficacy Against Melanoma Cells.

AAPS PharmSciTech 2020 Nov 4;21(8):304. Epub 2020 Nov 4.

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

Hispolon is a small molecular weight polyphenol that has antioxidant, anti-inflammatory, and anti-proliferative activities. Our recent study has demonstrated hispolon as a potent apoptosis inducer in melanoma cell lines. Doxorubicin is a broad spectrum first-line treatment for various kinds of cancers. In this study, co-delivery of doxorubicin and hispolon using a liposomal system in B16BL6 melanoma cell lines for synergistic cytotoxic effects was investigated. Liposomes were prepared using a lipid film hydration method and loaded with doxorubicin or hispolon. The formulations were characterized for particle size distribution, release profile, and encapsulation efficiency (EE). In addition, in vitro cytotoxicity, in vitro cell apoptosis, and cellular uptake were evaluated. Liposomes exhibited small particle size (mean diameter ~ 100 nm) and narrow size distribution (polydispersity index (< 0.2) and high drug EE% (> 90%). The release from liposomes showed slower release compared to free drug solution as an additional time required for the release of drug from the liposome lipid bilayer. Liposome loaded with doxorubicin or hispolon exhibited significantly higher cytotoxicity against B16BL6 melanoma cells as compared to doxorubicin solution or hispolon solution. Likewise, co-delivery of hispolon and doxorubicin liposomes showed two-fold and three-fold higher cytotoxicity, as compared to hispolon liposomes or doxorubicin liposomes, respectively. In addition, co-delivery of doxorubicin and hispolon in liposomes enhanced apoptosis more than the individual drugs in the liposome formulation. In conclusion, the co-delivery of hispolon and doxorubicin could be a promising therapeutic approach to improve clinical outcomes against melanoma.
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http://dx.doi.org/10.1208/s12249-020-01846-2DOI Listing
November 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

Nothing Ventured, Nothing Gained: Regulations Cripple Potentially Life-Saving Research of Illicit Substances.

ACS Chem Neurosci 2020 05 12;11(10):1382-1384. Epub 2020 May 12.

Department of Anatomy, Physiology and Pharmacology, Auburn University, Auburn, Alabama 36849, United States.

Modern day research, in an attempt to determine the potential therapeutic and adverse effects of illicit substances, is a growing field, but one that faces many regulatory challenges. Due to the potential abuse of illicit substances such as Cannabis, 3,4-methylenedioxymethamphetamine (MDMA), lysergic acid diethylamide (LSD) and psilocybin, regulations have been conceived with the intent of preventing harm and addiction. However, these regulations have also become a major barrier for the scientific community as they suffocate attempts of the scientists to acquire illicit substances for research purposes. Therefore, it is imperative to modify the current regulations of drug scheduling, leading to a reclassification of illicit substances that would allow for extensive testing in research settings. This reclassification effort could advance the potentially life-saving research of illicit substances.
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http://dx.doi.org/10.1021/acschemneuro.0c00241DOI Listing
May 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

Concurrent nicotine exposure to prenatal alcohol consumption alters the hippocampal and cortical neurotoxicity.

Heliyon 2020 Jan 8;6(1):e03045. Epub 2020 Jan 8.

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

Aims: This study investigated the neurotoxic effects of prenatal alcohol and nicotine exposure in the cortex and hippocampus of rodents.

Main Methods: Behavioral alterations, electrophysiological changes, and biochemical markers associated with cholinergic neurotransmission, neural oxidative stress, mitochondrial function, and apoptosis were evaluated.

Key Findings: Prenatal alcohol exposure induced the generation of ROS, nitrite and lipid peroxide, decreased mitochondrial Complex-I and IV activities, increased Caspase-1 and 3 activities, had no effect on cholinergic neurotransmission, increased expression of PSD-95, decreased LTP and decreased performance on spatial memory tasks. However, nicotine exposure, in addition to alcohol exposure, was found to mitigate the negative effects of alcohol alone on ROS generation and spatial memory task performances. Furthermore, we also studied the role of ILK in prenatal alcohol and nicotine exposure.

Significance: Prenatal Smoking and/or drinking is a major health concern around the world. Thus, our current study may lead to better insights into the molecular mechanisms of fetal alcohol and nicotine exposure on the developing offspring.
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http://dx.doi.org/10.1016/j.heliyon.2019.e03045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953639PMC
January 2020

Adverse pharmacokinetic interactions between illicit substances and clinical drugs.

Drug Metab Rev 2020 02 11;52(1):44-65. Epub 2019 Dec 11.

Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.

Adverse pharmacokinetic interactions between illicit substances and clinical drugs are of a significant health concern. Illicit substances are taken by healthy individuals as well as by patients with medical conditions such as mental illnesses, acquired immunodeficiency syndrome, diabetes mellitus and cancer. Many individuals that use illicit substances simultaneously take clinical drugs meant for targeted treatment. This concomitant usage can lead to life-threatening pharmacokinetic interactions between illicit substances and clinical drugs. Optimal levels and activity of drug-metabolizing enzymes and drug-transporters are crucial for metabolism and disposition of illicit substances as well as clinical drugs. However, both illicit substances and clinical drugs can induce changes in the expression and/or activity of drug-metabolizing enzymes and drug-transporters. Consequently, with concomitant usage, illicit substances can adversely influence the therapeutic outcome of coadministered clinical drugs. Likewise, clinical drugs can adversely affect the response of coadministered illicit substances. While the interactions between illicit substances and clinical drugs pose a tremendous health and financial burden, they lack a similar level of attention as drug-drug, food-drug, supplement-drug, herb-drug, disease-drug, or other substance-drug interactions such as alcohol-drug and tobacco-drug interactions. This review highlights the clinical pharmacokinetic interactions between clinical drugs and commonly used illicit substances such as cannabis, cocaine and 3, 4-Methylenedioxymethamphetamine (MDMA). Rigorous efforts are warranted to further understand the underlying mechanisms responsible for these clinical pharmacokinetic interactions. It is also critical to extend the awareness of the life-threatening adverse interactions to both health care professionals and patients.
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http://dx.doi.org/10.1080/03602532.2019.1697283DOI Listing
February 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

Doxorubicin-induced neurotoxicity is associated with acute alterations in synaptic plasticity, apoptosis, and lipid peroxidation.

Toxicol Mech Methods 2019 Jul 18;29(6):457-466. Epub 2019 Jun 18.

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

Cognitive deficits are commonly reported by patients following treatment with chemotherapeutic agents. Anthracycline-containing chemotherapy regimens are associated with cognitive impairment and reductions in neuronal connectivity in cancer survivors, and doxorubicin (Dox) is a commonly used anthracycline. Although it has been reported that Dox distribution to the central nervous system (CNS) is limited, considerable Dox concentrations are observed in the brain with co-administration of certain medications. Additionally, pro-inflammatory cytokines, which are overproduced in cancer or in response to chemotherapy, can reduce the integrity of the blood-brain barrier (BBB). Therefore, the aim of this study was to evaluate the acute neurotoxic effects of Dox on hippocampal neurons. In this study, we utilized a hippocampal cell line (H19-7/IGF-IR) along with rodent hippocampal slices to evaluate the acute neurotoxic effects of Dox. Hippocampal slices were used to measure long-term potentiation (LTP), and expression of proteins was determined by immunoblotting. Cellular assays for mitochondrial complex activity and lipid peroxidation were also utilized. We observed reduction in LTP in hippocampal slices with Dox. In addition, lipid peroxidation was increased as measured by thiobarbituric acid reactive substances content indicating oxidative stress. Caspase-3 expression was increased indicating an increased propensity for cell death. Finally, the phosphorylation of signaling molecules which modulate LTP including extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase, and Akt were increased. This data indicates that acute Dox exposure dose-dependently impairs synaptic processes associated with hippocampal neurotransmission, induces apoptosis, and increases lipid peroxidation leading to neurotoxicity.
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http://dx.doi.org/10.1080/15376516.2019.1600086DOI Listing
July 2019

PPAR-δ Activation Ameliorates Diabetes-Induced Cognitive Dysfunction by Modulating Integrin-linked Kinase and AMPA Receptor Function.

J Am Coll Nutr 2019 Nov-Dec;38(8):693-702. Epub 2019 Apr 22.

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

An estimated 9% of the American population experiences type II diabetes mellitus (T2DM) due to diet or genetic predisposition. Recent reports indicate that patients with T2DM are at increased risk for cognitive dysfunctions, as observed in conditions like Alzheimer's disease (AD). In addition, AD is the leading cause of dementia, highlighting the urgency of developing novel therapeutic targets for T2DM-induced cognitive deficits. The peroxisome proliferator activated receptor-δ (PPAR-δ) is highly expressed in the brain and has been shown to play an important role in spatial memory and hippocampal neurogenesis. However, the effect of PPAR-δ agonists on T2DM-induced cognitive impairment has not been explored. In this study, the effects of GW0742 (a selective PPAR-δ agonist) on hippocampal synaptic transmission, plasticity, and spatial memory were investigated in the mouse model of T2DM. Oral administration of GW0742 for 2 weeks significantly improved hippocampal long-term potentiation. In addition, GW0742 effectively prevented deficits in hippocampal dependent spatial memory in mice. PPAR-δ-mediated improvements in synaptic plasticity and behavior were accompanied by a significant recovery in hippocampal α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated synaptic transmission. Our findings suggest that activation of PPAR-δ might ameliorate T2DM-induced impairments in hippocampal synaptic plasticity and memory.
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http://dx.doi.org/10.1080/07315724.2019.1598307DOI Listing
September 2020

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

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

Dopaminergic neurotoxic effects of 3-TFMPP derivatives.

Life Sci 2018 Sep 29;209:357-369. Epub 2018 Jul 29.

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

Designer drugs are synthetically formulated to mimic the psychostimulatory effects of an original controlled/illegal drug of abuse. Designer drugs have similar chemical structure or functional analog as compared to existing controlled psychostimulatory drugs. There is a substantial rise in the production and use of designer drugs globally. Piperazine designer drugs were synthesized as an alternative to MDMA and have shown to induce numerous toxic effects leading to huge health, safety, law enforcement & monetary problems, and lethality. Currently, there are very few studies on the dopaminergic neurotoxicity of 1-(3-trifluoromethylphenyl) piperazine (3-TFMPP) and its derivatives (structural congeners). N27 rat dopaminergic neurons are valid cells to investigate the neurotoxic effects and establish the neurotoxic mechanisms of various substances. In the current study, we studied the time and dose-dependent neurotoxicity mechanisms of dopaminergic neurotoxicity of 3-TFMPP (parent compound) and its derivatives (2-TFMPP, 4-TFMPP). TFMPP derivatives-induced significant neurotoxicity (induced dopaminergic neuronal death. TFMPP derivatives-induced oxidative stress, mitochondrial dysfunction, apoptosis and decreased tyrosine hydroxylase expression. If the use of designer drugs are not strictly regulated and restricted around the world, this can lead to numerous central and peripheral disorders leading to a liability to the current and future society.
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http://dx.doi.org/10.1016/j.lfs.2018.07.052DOI Listing
September 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

Streptozotocin induced hyperglycemia stimulates molecular signaling that promotes cell cycle reentry in mouse hippocampus.

Life Sci 2018 Jul 8;205:131-135. Epub 2018 May 8.

Department of Biological and Environmental Sciences, Texas A&M University-Commerce, Commerce, TX 75429-3011, United States. Electronic address:

Aims: Cerebral atrophy resulting from neurodegeneration is highly prevalent in individuals with diabetes; however, the underlying mechanisms for diabetic neurodegeneration are not fully understood. Here we hypothesized that hyperglycemia induces molecular signaling that favors induction of proliferation in post mitotic, fully differentiated hippocampal neurons.

Materials And Methods: Streptozotocin (150 mg/kg) was intraperitoneally injected to four months old male mice to induce diabetes. Hippocampal tissue was subjected to molecular analysis of wingless-related integration site, extracellular signal regulated kinase, and brain derived neurotrophic factor signaling, and cell cycle regulation.

Key Findings: Hyperglycemia did not alter wingless-related integration site signaling or cyclin E levels in the hippocampus. There were reductions in extracellular signal regulated kinase activation and brain derived neurotrophic factor levels along with elevated cyclin D1 levels.

Significance: These findings indicate that hyperglycemic conditions can stimulate cell cycle progression in the hippocampus in vivo. These new insights into the disease mechanisms could support the development of novel therapeutics aimed to provide neuroprotection in diabetic patients.
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http://dx.doi.org/10.1016/j.lfs.2018.05.019DOI Listing
July 2018

Evaluation of behavioral parameters, hematological markers, liver and kidney functions in rodents exposed to Deepwater Horizon crude oil and Corexit.

Life Sci 2018 Apr 21;199:34-40. Epub 2018 Feb 21.

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

The 2010 Deepwater Horizon (DWH) oil spill is the largest marine oil spill in US history. In the aftermath of the spill, the response efforts used a chemical dispersant, Corexit, to disperse the oil spill. The health impacts of crude oil and Corexit mixture to humans, mammals, fishes, and birds are mostly unknown. The purpose of this study is to investigate the in vivo effects of DWH oil, Corexit, and oil-Corexit mixture on the general behavior, hematological markers, and liver and kidney functions of rodents. C57 Bl6 mice were treated with DWH oil (80 mg/kg) and/or Corexit (95 mg/kg), and several hematological markers, lipid profile, liver and kidney functions were monitored. The results show that both DWH oil and Corexit altered the white blood cells and platelet counts. Moreover, they also impacted the lipid profile and induced toxic effects on the liver and kidney functions. The impacts were more pronounced when the mice were treated with a mixture of DWH-oil and Corexit. This study provides preliminary data to elucidate the potential toxicological effects of DWH oil, Corexit, and their mixtures on mammalian health. Residues from the DWH spill continue to remain trapped along various Gulf Coast beaches and therefore further studies are needed to fully understand their long-term impacts on coastal ecosystems.
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http://dx.doi.org/10.1016/j.lfs.2018.02.028DOI Listing
April 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

Immunological alteration & toxic molecular inductions leading to cognitive impairment & neurotoxicity in transgenic mouse model of Alzheimer's disease.

Life Sci 2017 May 9;177:49-59. Epub 2017 Mar 9.

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

Aims: Inflammation is considered to be one of the crucial pathological factors associated with the development of Alzheimer's disease, although supportive experimental evidence remains undiscovered. Therefore, the current study was carried out to better understand and establish the pathophysiological involvement of chronic inflammation in a double transgenic mouse model of Alzheimer's disease.

Main Methods: We analyzed amyloid-beta deposition, oxidative stress, biochemical, neurochemical and immunological markers in a 10month old (APΔE9) mouse model. Memory functions were assessed by behavioral testing followed by measurement of synaptic plasticity via extracellular field recordings.

Key Findings: Substantial increases in amyloid-beta levels, beta-secretase activity, and oxidative stress, along with significant neurochemical alterations in glutamate and GABA levels were detected in the brain of APΔE9 mice. Interestingly, marked elevations of pro-inflammatory cytokines in whole brain lysate of APΔE9 mice were observed. Flow cytometric analysis revealed a higher frequency of CD4+ IL-17a and IFN-γ secreting T-cells in APΔE9 brain, indicating a robust T-cell infiltration and activation. Behavioral deficits in learning and memory tasks, along with impairment in long-term potentiation and associated biochemical changes in the expression of glutamatergic receptor subunits were evident.

Significance: Thus, this study establishes the role by which oxidative stress, alterations in glutamate and GABA levels and inflammation increases hippocampal and cortical neurotoxicity resulting in the cognitive deficits associated with Alzheimer's disease.
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http://dx.doi.org/10.1016/j.lfs.2017.03.004DOI Listing
May 2017

Altered AMPA receptor expression plays an important role in inducing bidirectional synaptic plasticity during contextual fear memory reconsolidation.

Neurobiol Learn Mem 2017 Mar 27;139:98-108. Epub 2016 Dec 27.

Department of Drug Discovery and Development, 4306 Walker Building, Auburn University, AL 36849, United States.

Retrieval of a memory appears to render it unstable until the memory is once again re-stabilized or reconsolidated. Although the occurrence and consequences of reconsolidation have received much attention in recent years, the specific mechanisms that underlie the process of reconsolidation have not been fully described. Here, we present the first electrophysiological model of the synaptic plasticity changes underlying the different stages of reconsolidation of a conditioned fear memory. In this model, retrieval of a fear memory results in immediate but transient alterations in synaptic plasticity, mediated by modified expression of the glutamate receptor subunits GluA1 and GluA2 in the hippocampus of rodents. Retrieval of a memory results in an immediate impairment in LTP, which is enhanced 6h following memory retrieval. Conversely, memory retrieval results in an immediate enhancement of LTD, which decreases with time. These changes in plasticity are accompanied by decreased expression of GluA2 receptor subunits. Recovery of LTP and LTD correlates with progressive overexpression of GluA2 receptor subunits. The contribution of the GluA2 receptor was confirmed by interfering with receptor expression at the postsynaptic sites. Blocking GluA2 endocytosis restored LTP and attenuated LTD during the initial portion of the reconsolidation period. These findings suggest that altered GluA2 receptor expression is one of the mechanisms that controls different forms of synaptic plasticity during reconsolidation.
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http://dx.doi.org/10.1016/j.nlm.2016.12.013DOI Listing
March 2017

Evaluating the neurotoxic effects of Deepwater Horizon oil spill residues trapped along Alabama's beaches.

Life Sci 2016 Jun 4;155:161-6. Epub 2016 May 4.

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

Aims: The Deepwater Horizon oil spill (also known as the BP spill) is one of the largest oil spills in the U.S.

History: To manage the spill, BP used an oil spill dispersant (Corexit 9500A) to disperse the oil. However, a portion of undispersed oil eventually got emulsified and interacted with near shore sediments along the Alabama shoreline and sank to the bottom forming tarmats, also known as submerged residual oil mats (SRMs). Natural shoreline transport processes have often broken these tarmats to form smaller oil fragments, known as surface residual oil balls (SRBs) or tarballs. The long-term human and the ecological health impacts of various toxic chemicals trapped in tarmat deposits are currently unknown. The purpose of this study is to investigate the in vitro cytotoxic effects of the chemicals trapped in tarmat fragments using hippocampal (neuron), kidney (nephron) and epithelial cells.

Main Methods: Water accommodated fraction (WAF) of tarmat fragments was used in this study. Cytotoxicity was elucidated by the MTT assay and cellular morphology assessment. Markers of oxidative stress and apoptosis were assessed to study the toxicity effects. Statistical analysis was performed using Sigma-stat.

Key Findings: Tarmat WAF induced dose-dependent cellular toxicity. Chemicals trapped in tarmat WAF inhibited cell viability in the hippocampal (H19), kidney (HEK-293) and epithelial (MCF-10A) cells. Tarmat WAF also generated reactive oxygen species and increased activity of superoxide dismutase in hippocampal cells.

Significance: The study has provided preliminary data to elucidate the toxic potential of BP oil spill residues trapped along the Alabama shoreline.
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http://dx.doi.org/10.1016/j.lfs.2016.05.002DOI Listing
June 2016

Methamphetamine-induced dopaminergic toxicity prevented owing to the neuroprotective effects of salicylic acid.

Life Sci 2016 Jun 27;154:24-9. Epub 2016 Feb 27.

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

Aims: Methamphetamine (Schedule-II drug, U.S. Drug Enforcement Administration) is one of the most abused illicit drug following cocaine, marijuana, and heroin in the USA. There are numerous health impairments and substantial economic burden caused by methamphetamine abuse. Salicylic acid, potent anti-inflammatory drug and a known neuroprotectant has shown to protect against toxicity-induced by other dopaminergic neurotoxins. Hence, in this study we investigated the neuroprotective effects of salicylic acid against methamphetamine-induced toxicity in mice.

Main Methods: The current study investigated the effects of sodium salicylate and/or methamphetamine on oxidative stress, monoamine oxidase, mitochondrial complex I & IV activities using spectrophotometric and fluorimetric methods. Behavioral analysis evaluated the effect on movement disorders-induced by methamphetamine. Monoaminergic neurotransmitter levels were evaluated using high pressure liquid chromatography-electrochemical detection.

Key Findings: Methamphetamine caused significant generation of reactive oxygen species and decreased complex-I activity leading to dopamine depletion. Striatal dopamine depletion led to significant behavioral changes associated with movement disorders. Sodium salicylate (50 & 100mg/kg) significantly scavenged reactive oxygen species, blocked mitochondrial dysfunction and exhibited neuroprotection against methamphetamine-induced neurotoxicity. In addition, sodium salicylate significantly blocked methamphetamine-induced behavioral changes related to movement abnormalities.

Significance: One of the leading causative theories in nigral degeneration associated with movement disorders such as Parkinson's disease is exposure to stimulants, drugs of abuse, insecticide and pesticides. These neurotoxic substances can induce dopaminergic neuronal insult by oxidative stress, apoptosis, mitochondrial dysfunction and inflammation. Salicylic acid due to its antioxidant and anti-inflammatory effects could provide neuroprotection against the stimulants or drugs of abuse.
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http://dx.doi.org/10.1016/j.lfs.2016.02.072DOI Listing
June 2016

The role of frataxin in doxorubicin-mediated cardiac hypertrophy.

Am J Physiol Heart Circ Physiol 2015 Sep 24;309(5):H844-59. Epub 2015 Jul 24.

Department of Drug, Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, Alabama;

Doxorubicin (DOX) is a highly effective anti-neoplastic agent; however, its cumulative dosing schedules are clinically limited by the development of cardiotoxicity. Previous studies have attributed the cause of DOX-mediated cardiotoxicity to mitochondrial iron accumulation and the ensuing reactive oxygen species (ROS) formation. The present study investigates the role of frataxin (FXN), a mitochondrial iron-sulfur biogenesis protein, and its role in development of DOX-mediated mitochondrial dysfunction. Athymic mice treated with DOX (5 mg/kg, 1 dose/wk with treatments, followed by 2-wk recovery) displayed left ventricular hypertrophy, as observed by impaired cardiac hemodynamic performance parameters. Furthermore, we also observed significant reduction in FXN expression in DOX-treated animals and H9C2 cardiomyoblast cell lines, resulting in increased mitochondrial iron accumulation and the ensuing ROS formation. This observation was paralleled in DOX-treated H9C2 cells by a significant reduction in the mitochondrial bioenergetics, as observed by the reduction of myocardial energy regulation. Surprisingly, similar results were observed in our FXN knockdown stable cell lines constructed by lentiviral technology using short hairpin RNA. To better understand the cardioprotective role of FXN against DOX, we constructed FXN overexpressing cardiomyoblasts, which displayed cardioprotection against mitochondrial iron accumulation, ROS formation, and reduction of mitochondrial bioenergetics. Lastly, our FXN overexpressing cardiomyoblasts were protected from DOX-mediated cardiac hypertrophy. Together, our findings reveal novel insights into the development of DOX-mediated cardiomyopathy.
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http://dx.doi.org/10.1152/ajpheart.00182.2015DOI Listing
September 2015