Effect of levetiracetam on DNA oxidation and glutathione content in a temporal lobe epilepsy model.

Levetiracetam (LEV) is a drug commonly used as an anticonvulsant. However, recent evidence points to a possible role as an antioxidant. We previously demonstrated the antioxidant properties of LEV by significantly increasing catalase and superoxide dismutase activities and decreasing the hydrogen peroxide (H2O2) levels in the hippocampus of rats with temporal lobe epilepsy (TLE) showing scavenging properties against the hydroxyl radical. The aim of the present work was to evaluate, the effect of LEV on DNA oxidation, by determining 8­hydroxy­2­deoxyguanosine (8­OHdG) levels, and glutathione content, through reduced (GSH) and oxidized (GSSG) glutathione levels, in the hippocampus of rats with TLE. Male Wistar rats were assigned to the control (CTRL), CTRL+LEV, epileptic (EPI) and EPI+LEV groups. TLE was induced using the lithium­pilocarpine model. Thirteen weeks after TLE induction, LEV was administered for one week through osmotic pumps implanted subcutaneously. The determination of 8­OHdG, GSH and GSSG levels were measured using spectrophotometric methods. We showed that LEV alone significantly increased 8­OHdG and GSSG levels in the hippocampus of control rats compared to those in epileptic condition. No significant differences in GSH levels were observed. LEV could induce changes in the hippocampus increasing DNA oxidation and GSSG levels under nonepileptic condition but not protecting against the mitochondrial dysfunction observed in TLE probably by mechanisms related to changes in chromatin structure, neuroinflammation and alterations in redox components.

Regulation of ferroptosis and ACSL4-15LO1 pathway contributed to the anti-asthma effect of acupuncture.

Acupuncture has been frequently used in China for the treatment asthma for thousands of years. Ferroptosis was recently revealed to be involved in several pathological conditions including asthma. However, the detailed links between ferroptosis and airway inflammation in asthma, as well as the detailed regulation of acupuncture on these disorders remains unclear. Our results demonstrated that the non-haem Fe2+ level increased markedly in the lung tissue of mouse asthma model, and positively correlated with RL and IL-4 level in BALF. Furthermore, lipid peroxidation markers MDA and GSSG increased remarkably in OVA-induced experimental asthma mice. Up-regulation of lipid peroxidation associated proteins ACSL4 and15-LO1 was also observed in OVA-induced experimental asthma mice. To demonstrate the role of ferroptosis in asthma and the effect of acupuncture on these disorders, ferroptosis-induction agent erastin and ferroptosis-inhibition agent fer-1 were used, and our data demonstrated that erastin could augment lung inflammation and lipid peroxidation in OVA induced asthma model. Fer-1 was able to relieve AHR, lung inflammation, non-haem Fe2+ level, lipid peroxidation and ferroptosis related pathway ACSL4-15LO1 in OVA-induced experimental asthma mice. Acupuncture treatment alleviated RL, lung inflammation as well as type 2 cytokines IL-4 and IL-13 levels induced by OVA inhalation. What's more, acupuncture significantly reduced the MDA and GSSG levels, the non-haem Fe2+ level and ACSL4-15-LO1 proteins expression. Acupuncture also relieved erastin-induced exacerbation in lung inflammation and lipid peroxidation in ferroptosis. Acupuncture treatment could relieve ferroptosis related exacerbation in airway inflammation. Our study provided insights into the underlying mechanisms for the protective effects of acupuncture and highlighted a therapeutic potential of acupuncture treatment in the attenuation of lipid peroxidation and ferroptosis in asthma.

Early time course of oxidative stress in hippocampal synaptosomes and cognitive loss following impaired insulin signaling in rats: Development of sporadic Alzheimer's disease.

Oxidative stress, caused by impaired insulin signaling, plays a pivotal role in the pathogenesis of sporadic Alzheimer's disease (sAD). We investigated the oxidative stress parameters in the synaptosomes prepared from the hippocampus tissue in order to identify their potential role in sAD development in intraperitoneal (IP) and intracerebroventricular (ICV) streptozotocin (STZ) injections models of insulin signaling impairment. Rats were harvested 1, 3, or 6 weeks post treatment. Spatial learning and memory, several antioxidants and oxidative stress markers were analyzed. Results showed a significant deficit in learning and memory in rats injected with STZ through IP and ICV routes. Glutathione, glutathione/oxidized glutathione, glutathione S-transferase, glutathione peroxidase, glutathione reductase, catalase, superoxide dismutase(SOD)-total, Zn/Cu(SOD), Mn/Fe(SOD) are significantly decreased in IP-STZ and ICV-STZ groups at 1, 3, and 6 weeks after STZ injection. Oxidized glutathione, thiobarbituric acid reactive species, glucose 6-Phosphate dehydrogenase, protein carbonyls, 4-Hydroxynonenal, and 3-Nitrotyrosine are significantly increased in IP-STZ and ICV-STZ groups at 1,3, and 6 weeks after STZ injection. Changes in oxidative stress parameters in ICV-STZ groups are greater than IP-STZ groups. STZ treatment induced cognitive impairments by 3-W and 6-W, and it was significantly correlated with the extent of oxidative damage. In conclusion, STZ administration through ICV route is deleterious in causing early synaptosomal oxidative damage that exacerbated with time and correlated with cognitive impairments. Our data implicate the involvement of oxidative stress as an early feature of sAD and provide insights into the behavioral and biochemical changes over the course of disease development.

NOV-002, a mimetic of glutathione disulfide.

BACKGROUND: Oxidative signaling to modulate redox-sensitive cell functions is a heretofore unexploited approach to developing new drugs for poorly treated oncology indications, where current therapies are often only palliative and accompanied by severe toxicities. OBJECTIVE: Clinical and non-clinical findings with NOV-002 (a mimetic of glutathione disulfide that represents such an approach) are reviewed and evaluated. METHODS: Published data on NOV-002 along with unpublished information from the drug's sponsor were reviewed. Literature analysis also focused on protein S-glutathionylation as a regulatory mechanism, particularly in relation to cell signaling, proliferation and cytoskeletal architecture. RESULTS/CONCLUSION: NOV-002 is a mechanistically novel agent with potential for ameliorating hematologic toxicity and enhancing efficacy when used in combination with standard chemotherapy to treat cancer patients.