m-trifluoromethyl-diphenyl-diselenide and Disease-Models--Animal

Chronic pain and depression are two complex states that often coexist in the clinical setting and traditional antidepressants and analgesics have shown limited clinical efficacy. There is an intricate communication between the immune system and the central nervous system and inflammation has been considered a common mediator of pain-depression comorbidity. This study evaluated the effect of m-trifluoromethyl diphenyl diselenide [(m-CF3-PhSe)2], an organoselenium compound that has been reported to have both antinociceptive and antidepressant-like actions, in the comorbidity of chronic pain and depression induced by partial sciatic nerve ligation (PSNL) in an inflammatory approach. Mice were submitted to PSNL during 4weeks and treated with (m-CF3-PhSe)2 acutely (0.1-10mg/kg, i.g.) or subchronically (0.1mg/kg, i.g., once a day during the 3rd and 4th weeks). Both treatments prevented PSNL-increased pain sensitivity and depressive-like behavior observed in Von-Frey hair (VFH) and forced swimming (FST) tests, respectively. These effects could be mainly associated with an anti-inflammatory action of (m-CF3-PhSe)2 which reduced the levels of pro-inflammatory cytokines, NF-κB and COX-2, and p38 MAPK activation that were increased by PSNL. (m-CF3-PhSe)2 also increased the BDNF levels and reduced glutamate release and 5-HT uptake altered by PSNL. Although acute and subchronic treatments with (m-CF3-PhSe)2 prevented these alterations induced by PSNL, the best results were found when (m-CF3-PhSe)2 was subchronically administered to mice. Considering the potential common mechanisms involved in the comorbidity of inflammation-induced depression and chronic pain, the results found in this study indicate that (m-CF3-PhSe)2 could become an interesting molecule to treat long-lasting pathological pain associated with depression.

Topics: Adrenocorticotropic Hormone; Animals; Antidepressive Agents; Brain; Corticosterone; Cytokines; Depression; Disease Models, Animal; Functional Laterality; Glutamic Acid; Hyperalgesia; Male; Mice; Motor Activity; Neuralgia; Organosilicon Compounds; Peripheral Nerve Injuries; Serotonin; Swimming; Synaptosomes; Tritium

Glutaric acidemia type I (GA-I) is an inherited metabolic disease characterized by accumulation of glutaric acid (GA) and seizures. The intrastriatal GA administration in rats has been used as an animal model to mimic seizures presented by glutaric acidemic patients. m-Trifluoromethyl diphenyl diselenide, (m-CF(3) -C(6) H(4) Se)(2) , is an organoselenium compound that protects against seizures induced by pentylenetetrazole in mice. Thus, the aim of this study was to investigate whether (m-CF(3) -C(6) H(4) Se)(2) is effective against GA-induced seizures and oxidative stress in rat pups 21 days of age. Our findings demonstrate that (m-CF(3) -C(6) H(4) Se)(2) preadministration (50 mg/kg; p.o.) protected against the reduction in latency and the increased duration of GA (1.3 μmol/right striatum)-induced seizures in rat pups. In addition, (m-CF(3) -C(6) H(4) Se)(2) protected against the increase in reactive species generation and the reduction in antioxidant defenses glutathione peroxidase and glutathione S-transferase activities induced by GA. By contrast, no change in glutathione reductase or catalase activities was found. In addition, (m-CF(3) -C(6) H(4) Se)(2) was effective in protecting against inhibition of Na(+) ,K(+) -ATPase activity caused by GA in striatum of rat pups. This study showed for the first time that GA administration caused an increase in [(3) H]GABA uptake from striatum slices of rat pups and that (m-CF(3) -C(6) H(4) Se)(2) preadministration protected against this increase. A positive correlation between duration of seizures and [(3) H]GABA uptake levels was demonstrated. The results indicate that (m-CF(3) -C(6) H(4) Se)(2) protected against GA-induced seizures. Moreover, these findings suggest that the protection against oxidative stress, the inhibition of Na(+) ,K(+) -ATPase activity, and the increase in [(3) H]GABA uptake are possible mechanisms for the potential anticonvulsant action of (m-CF(3) -C(6) H(4) Se)(2).

Topics: Amino Acid Metabolism, Inborn Errors; Animals; Anticonvulsants; Brain Diseases, Metabolic; Disease Models, Animal; gamma-Aminobutyric Acid; Glutarates; Glutaryl-CoA Dehydrogenase; Male; Organosilicon Compounds; Oxidative Stress; Rats; Rats, Wistar; Seizures