Ayman G. Mustafa

Antioxidant therapies for traumatic brain injury

SummaryFree radical-induced oxidative damage reactions, and membrane lipid peroxidation (LP), in particular, are among the best validated secondary injury mechanisms in preclinical traumatic brain injury (TBI) models. In addition to the disruption of the membrane phospholipid architecture, LP results in the formation of cytotoxic aldehyde-containing products that bind to cellular proteins and impair their normal functions. This article reviews the progress of the past three decades in regard to the preclinical discovery and attempted clinical development of antioxidant drugs designed to inhibit free radical-induced LP and its neurotoxic consequences via different mechanisms including the O2·− scavenger Superoxide dismutase and the lipid peroxidation inhibitor tirilazad. In addition, various other antioxidant agents that have been shown to have efficacy in preclinical TBI models are briefly presented, such as the LP inhibitors U83836E, resveratrol, curcumin, OPC-14177, and lipoic acid; the iron chelator deferoxamine and the nitroxide-containing antioxidants, such as α-phenyl-tert-butyl nitrone and tempol. A relatively new antioxidant mechanistic strategy for acute TBI is aimed at the scavenging of aldehydic LP byproducts that are highly neurotoxic with “carbonyl scavenging” compounds. Finally, it is proposed that the most effective approach to interrupt posttraumatic oxidative brain damage after TBI might involve the combined treatment with mechanistically complementary antioxidants that simultaneously scavenge LP-initiating free radicals, inhibit LP propagation, and lastly remove neurotoxic LP byproducts.

Mitochondrial protection after traumatic brain injury by scavenging lipid peroxyl radicals

J. Neurochem. (2010) 114, 271–280.

Pharmacological inhibition of lipid peroxidation attenuates calpain-mediated cytoskeletal degradation after traumatic brain injury

J. Neurochem. (2011) 117, 579–588.

A pharmacological analysis of the neuroprotective efficacy of the brain- and cell-permeable calpain inhibitor MDL-28170 in the mouse controlled cortical impact traumatic brain injury model.

The cytoskeletal and neuronal protective effects of early treatment with the blood-brain barrier- and cell-permeable calpain inhibitor MDL-28170 was examined in the controlled cortical impact (CCI) traumatic brain injury (TBI) model in male CF-1 mice. This was preceded by a dose-response and pharmacodynamic evaluation of IV or IP doses of MDL-28170 with regard to ex vivo inhibition of calpain 2 activity in harvested brain homogenates. From these data, we tested the effects of an optimized MDL-28170 dosing regimen on calpain-mediated degradation of the neuronal cytoskeletal protein α-spectrin in cortical or hippocampal tissue of mice 24 h after CCI-TBI (1.0 mm depth, 3.5 m/sec velocity). With treatment initiated at 15 min post-TBI, α-spectrin degradation was significantly reduced by 40% in hippocampus and 44% in cortex. This effect was still observed with a 1-h but not a 3-h post-TBI delay. The cytoskeletal protection is most likely taking place in neurons surrounding the area of mainly necrotic degeneration, since MDL-28170 did not reduce hemispheric lesion volume as measured by the aminocupric silver staining method. This lack of effect on lesion volume has been seen with other calpain inhibitors, which suggests that pharmacological calpain inhibition by itself, while able to reduce axonal injury, may not be able to produce a measurable reduction in lesion volume. This is in contrast to certain other neuroprotective mechanistic approaches such as the mitochondrial protectant cyclosporine A, which produces at least a partial decrease in lesion volume in the same model. Accordingly, the combination of a calpain inhibitor with a compound such as cyclosporine A may be needed to achieve the optimal degree of post-TBI neuroprotection.

Anatomy learning styles and strategies among Jordanian and Malaysian medical students: the impact of culture on learning anatomy

PurposeThe study aims to investigate anatomy learning styles and strategies of Jordanian and Malaysian medical students at the Jordan University of Science and Technology.MethodsThe study is a cross-sectional questionnaire-based study. Students’ responses for the questionnaire were numerically coded, and the results were analyzed to reveal statistically significant differences between Jordanian and Malaysian students.ResultsThe results showed that Jordanian medical students were less interested in using cadavers in learning anatomy than Malaysian medical students. However, similar to their Malaysian counterparts, they prefer to employ other tools to learn anatomy like plastinated models and Internet-based resources. In addition to the aforementioned tools, Malaysian students were more interested in using cross-sectional images and making their own revision cards. Both Jordanian and Malaysian medical students were more interested in learning anatomy through clinical cases, and by system rather than by region. Moreover, it was revealed that Jordanian medical students learn anatomy more efficiently when they formulate a general view of a particular topic. Both Jordanian and Malaysian medical students also relied on reciting definitions and memorizing facts to learn anatomy. The study also reported significant differences between Jordanian and Malaysian students’ perspectives on learning anatomy.ConclusionsThe findings of the study suggest that Jordanian and Malaysian medical students posses different cultures of learning. Jordanian anatomy instructors need to consider these different learning cultures when they prepare their instructional methods and teaching materials to fulfill the educational needs of their culturally diverse students.

Morphological changes in palatal rugae patterns following orthodontic treatment

This study investigated the morphometric changes that occur in palatal rugae during orthodontic treatment. The potential impact of these changes on the individuality of the palatal rugae patterns and on the use of palatal rugae patterns in human identification was also explored. Fifty pairs of pre- and post-orthodontic treatment dental casts were used. The palatal rugae patterns were compared between each pre-treatment cast and its post-treatment counterpart to reveal any morphometric changes. In addition, the individuality of the pre- and post-treatment sets of the casts was evaluated. Finally, a matching test of the palatal rugae patterns was performed in which the ability to match each post-treatment cast with its duplicate was compared with the ability to match that post-treatment cast with its pre-treatment counterpart. Statistical analysis of the results revealed the incidence of several morphometric changes, including segmentation (22%); unification (20%); changes in orientation (6%), shape (6%), and length (28%); anteroposterior displacement of the medial (54%) and lateral (60%) end of the ruga; and mediolateral displacement of the medial end of ruga (20%). The individuality of the palatal rugae patterns was confirmed in both pre- and post-treatment sets of casts. Finally, the mean percentage of correct matches was found to be significantly higher when the post-treatment casts were matched with their duplicates compared to when they were matched with their pre-treatment counterparts. The study revealed that Orthodontic treatment induces various morphometric changes in the palatal rugae patterns. These changes may potentially complicate palatal rugae-based human identification.

Effect of oxidative stress on Rho kinase II and smooth muscle contraction in rat stomach

Recent studies have shown that both Rho kinase signaling and oxidative stress are involved in the pathogenesis of a number of human diseases, such as diabetes mellitus, hypertension, and atherosclerosis. However, very little is known about the effect of oxidative stress on the gastrointestinal (GI) smooth muscle Rho kinase pathway. The aim of the current study was to investigate the effect of oxidative stress on Rho kinase II and muscle contraction in rat stomach. The peroxynitrite donor 3-morpholinosydnonimine (SIN-1), hydrogen peroxide (H2O2), and peroxynitrite were used to induce oxidative stress. Rho kinase II expression and ACh-induced activity were measured in control and oxidant-treated cells via specifically designed enzyme-linked immunosorbent assay (ELISA) and activity assay kits, respectively. Single smooth muscle cell contraction was measured via scanning micrometry in the presence or absence of the Rho kinase blocker, Y-27632 dihydrochloride. All oxidant agents significantly increased ACh-induced Rho kinase II activity without affecting its expression level. Most important, oxidative stress induced by all three agents augmented ACh-stimulated muscle cell contraction, which was significantly inhibited by Y-27632. In conclusion, oxidative stress activates Rho kinase II and enhances contraction in rat gastric muscle, suggesting an important role in GI motility disorders associated with oxidative stress.

Tempol protects blood proteins and lipids against peroxynitrite-mediated oxidative damage

Oxidative stress is characterized by excessive production of various free radicals and reactive species among which, peroxynitrite is most frequently produced in several pathological conditions. Peroxynitrite is the product of the superoxide anion reaction with nitric oxide, which is reported to take place in the intravascular compartment. Several studies have reported that peroxynitrite targets red blood cells, platelets and plasma proteins, and induces various forms of oxidative damage. This in vitro study was designed to further characterize the types of oxidative damage induced in platelets and plasma proteins by peroxynitrite. This study also determined the ability of tempol to protect blood plasma and platelets against peroxynitrite-induced oxidative damage. The ability of various concentrations of tempol (25, 50, 75, and 100 µM) to antagonize peroxynitrite-induced oxidation was evaluated by measuring the levels of protein carbonyl groups and thiobarbituric-acid-reactive substances in experimental groups. Exposure of platelets and plasma to 100 µM peroxynitrite resulted in an increased levels of carbonyl groups and lipid peroxidation (P < 0.05). Tempol significantly inhibited carbonyl group formation in plasma and platelet proteins (P < 0.05). In addition, tempol significantly reduced the levels of lipid peroxidation in both plasma and platelet samples (P < 0.05). Thus, tempol has antioxidative properties against peroxynitrite-induced oxidative damage in blood plasma and platelets.

Fresh onion juice enhanced copulatory behavior in male rats with and without paroxetine-induced sexual dysfunction:

Onion (Allium cepa) is one of the most commonly cultivated species of the family Liliaceae, and has long been used in dietary and therapeutic applications. Treatment with fresh onion juice has been reported to promote testosterone production in male rats. Testosterone is the male sex hormone responsible for enhancing sexual libido and potency. This study aimed to investigate the effects of onion juice on copulatory behavior of sexually potent male rats and in male rats with paroxetine-induced sexual dysfunction. Sexually experienced male rats were divided into seven groups: a control group, three onion juice-treated groups, a paroxetine-treated group, and two groups treated with paroxetine plus different doses of onion juice. At the end of the treatments, sexual behavior parameters and testosterone levels were measured and compared among the groups. Administration of onion juice significantly reduced mount frequency and latency and increased the copulatory efficacy of potent male rats. In addition, administration of onion juice attenuated the prolonged ejaculatory latency period induced by paroxetine and increased the percentage of ejaculating rats. Serum testosterone levels increased significantly by onion juice administration. However, a significant reduction in testosterone because of paroxetine therapy was observed. This reduction was restored to normal levels by administration of onion juice. This study conclusively demonstrates that fresh onion juice improves copulatory behavior in sexually potent male rats and in those with paroxetine-induced sexual dysfunction by increasing serum testosterone levels.

The role of free radicals and reactive species following traumatic brain injury

Abstract Introduction Traumatic brain injury is a leading cause of mortality and morbidity worldwide. Even though the primary phase of traumatic brain injury is mechanical and not amenable to intervention, the secondary phase is composed of a cascade of pathological and biochemical mechanisms that culminate in loss of neuronal functions. Among these secondary mechanisms of injury is the excess generation of free radicals and reactive species. Many reports in the literature documented the formation of oxygen and nitrogen free radicals and reactive species following traumatic brain injury. The formation of these reactive species following traumatic brain injury was further validated by detecting their footprints in traumatised neural tissues such as lipid peroxidation and protein nitration and carbonylation. This review aims to highlight the post-traumatic generation of free radicals and reactive species and discuss their role in propagating other secondary injury cascades. Conclusion The formation of free radicals and reactive species is a significant event after traumatic brain injury and is implicated in accentuating other elements of the secondary injury cascades including mitochondrial dysfunction, Ca++ dysregulation and activation of cellular proteases. The significance of these reactive species has been validated by many reports showing the virtues of scavenging these reactive species and/or their reactive by-products as a potential cure for traumatic brain injury.