Ameliorative Effects of α-Tocopherol and/or Coenzyme Q10 on Phenytoin-Induced Cognitive Impairment in Rats: Role of VEGF and BDNF-TrkB-CREB Pathway.

Phenytoin is one of the most well-known antiepileptic drugs that cause cognitive impairment which is closely related to cAMP response element-binding protein (CREB) brain-derived neurotrophic factor (BDNF) signaling pathway. Moreover, vascular endothelial growth factor (VEGF), an endothelial growth factor, has a documented role in neurogenesis and neuronal survival and cognitive impairment. Therefore, this study aimed to investigate the influence of powerful antioxidants: α-Toc and CoQ10 alone or combined in the preservation of brain tissues and the maintenance of memory formation in phenytoin-induced cognitive impairment in rats. The following behavioral test novel object recognition and elevated plus maze were assessed after 14 days of treatment. Moreover, VEGF, BDNF, TrkB, and CREB gene expression levels in the hippocampus and prefrontal cortex were estimated using RT-PCR. Both α-Toc and CoQ10 alone or combined with phenytoin showed improvement in behavioral tests compared to phenytoin. Mechanistically, α-Toc and/or CoQ10 decreases the VEGF mRNA expression, while increases BDNF-TrKB-CREB mRNA levels in hippocampus and cortex of phenytoin-treated rats. Collectively, α-Toc and/or CoQ10 alleviated the phenytoin-induced cognitive impairment through suppressing oxidative damage. The underlying molecular mechanism of the treating compounds is related to the VEGF and enhancing BDNF-TrkB-CREB signaling pathway. Our study indicated the usefulness α-Toc or CoQ10 as an adjuvant to antiepileptic drugs with an advantage of preventing cognitive impairment and oxidative stress.

Molecular mechanisms of neuroprotective effect of adjuvant therapy with phenytoin in pentylenetetrazole-induced seizures: Impact on Sirt1/NRF2 signaling pathways.

Current anticonvulsant therapies are principally aimed at suppressing neuronal hyperexcitability to prevent or control the incidence of seizures. However, the role of oxidative stress processes in seizures led to the proposition that antioxidant compounds may be considered as promising candidates for limiting the progression of epilepsy. Accordingly, the aim of this study is to determine if coenzyme Q10 (CoQ10) and alpha-tocopherol (α-Toc) have a neuroprotective effect in rats against the observed oxidative stress and inflammation during seizures induced by pentylenetetrazole (PTZ) in rats, and to study their interactions with the conventional antiseizure drug phenytoin (PHT), either alone or in combination. Overall, the data revealed that α-Toc and CoQ10 supplementation can ameliorate PTZ-induced seizures and recommended that nuclear factor erythroid 2-related factor 2 (NRF2) and silencing information regulator 1 (Sirt1) signaling pathways may exemplify strategic molecular targets for seizure therapies. The results of the present study provide novel mechanistic insights regarding the protective effects of antioxidants and suggest an efficient therapeutic strategy to attenuate seizures. Additionally, concurrent supplementation of CoQ10 and α-Toc may be more effective than either antioxidant alone in decreasing inflammation and oxidative stress in both cortical and hippocampal tissues. Also, CoQ10 and α-Toc effectively reverse the PHT-mediated alterations in the brain antioxidant status when compared to PHT only.

Prophylactic L-arginine and ibuprofen delay the development of tactile allodynia and suppress spinal miR-155 in a rat model of diabetic neuropathy.

Diabetic neuropathy (DN) is a common complication of diabetes mellitus that is hardly reversible at the late stages. Since treatment of neuropathic pain is predominantly symptomatic, a prophylactic measure would be useful. Both ibuprofen and L-arginine exert antiallodynic effects on chronic constriction injury (CCI)-induced cold allodynia. Furthermore, ibuprofen is effective in CCI-induced mechanical allodynia. The aim of the study was to assess the antiallodynic effect of prophylactic ibuprofen and L-arginine in streptozotocin-induced DN in rats and to further investigate the role of spinal miR-155 and nitric oxide (NO) in this effect. Tactile allodynia was assessed weekly by von Frey filaments. Oral daily administration of ibuprofen, L-arginine and their combination, for 4 weeks starting 1 week after streptozotocin injection (ie, before the development of tactile allodynia), resulted in a significant decrease of tactile allodynia compared with the control diabetic group. This was evident in the fifth week of the experiment. The 3 treatments prevented the decrease in muscle fiber diameter and epidermal thickness, seen in the control diabetic group. Furthermore, ibuprofen, L-arginine and their combination prevented the increase in the spinal NO level and miRNA-155, seen in the control diabetic group. In conclusion, both ibuprofen and L-arginine delayed the development of behavioral and histologic changes of DN, with concomitant suppression of spinal miR-155 and NO level. L-arginine being tolerable may be useful prophylactically in diabetic patients.

Nitric oxide is involved in ibuprofen preemptive analgesic effect in the plantar incisional model of postsurgical pain in mice.

Control of postoperative pain is far from satisfactory. Yet, non-steroidal anti-inflammatory drugs (NSAIDs) remain an important choice. The production of nitric oxide (NO), which plays an important role in the development and maintenance of inflammatory hyperalgesia, is inhibited by NSAIDs. Monoamines also play a key role in the modulation of nociception. The aim of the present work is to study the involvement of NO and monoamines in the antinociceptive mechanism of ibuprofen in postsurgical pain in mice. Surgical incision resulted in mechanical allodynia and increased spinal NO levels. The nitric oxide synthase inhibitor l-NAME (50mg/kg), administered intraperitoneally (i.p.), 30min before the incision decreased the development of postsurgical mechanical allodynia and reduced spinal NO levels. Ibuprofen (100 and 300mg/kg, i.p.), administered 30min before the incision, dose-dependently decreased both spinal NO levels and the development of mechanical allodynia. Administration of ibuprofen (100mg/kg i.p.), 20min following surgery, did not significantly reduce spinal NO level and resulted in a smaller antiallodynic effect. l-Arginine (600mg/kg i.p.), administered 20min before ibuprofen administration, restored both spinal NO level and mechanical allodynia in ibuprofen-treated mice. The selective alpha-2 adrenoceptor blocker yohimbine (4mg/kg i.p.), administered 30min before ibuprofen, also blocked ibuprofen effect on both mechanical allodynia and spinal NO level. These results suggest that inhibition of NO synthesis is involved in the analgesic activity of ibuprofen in post-surgical pain. Alpha-2 adrenoceptors are also involved in the analgesic activity of ibuprofen and NO may be involved in this mechanism.

Ibuprofen suppresses depressive like behavior induced by BCG inoculation in mice: role of nitric oxide and prostaglandin.

Prostaglandins (PGs) and nitric oxide (NO) may be involved in the pathophysiology of depression. Since NSAIDs decrease PGs and NO production, they may have an antidepressant effect. The aim of the present work was to explore a possible antidepressant action of ibuprofen in the new model of Bacillus Calmette-Guerin (BCG) induced depression. Mice injected with BCG (10(7) CFU/mouse intraperitoneally) showed an increase in the total immobility time during the forced swim test (FST) and the tail suspension test (TST) and an increase in cerebral PGE2 and NO levels. Fluoxetine administered in drinking water at a dose of 80 mg/l, 5 days before BCG and for 2 more weeks resulted in significant decrease in total immobility time during FST and TST and in cerebral PGE2 and NO levels. Both ibuprofen (200 mg/l) and L-NAME (1 g/l) administered in drinking water 24 h before BCG and for 2 more weeks resulted in decrease in the total immobility time during FST and TST and in cerebral PGE2 and NO levels, which was comparable to fluoxetine's effect. On the other hand, l-arginine administered at a dose of 6 g/l in drinking water together with ibuprofen or fluoxetine reversed their effect on FST, TST and cerebral PGE2 and NO levels. Immunohistochemistry showed a decrease in COX-1 and i-NOS immunoreactivity in the CA1 and CA3 areas of the hippocampus following ibuprofen treatment. These results suggest that ibuprofen may have an antidepressant effect through inhibition of PGE2 and NO production, especially in depression secondary to chronic inflammation.