HOE-140, an antagonist of B2 receptor, protects against memory deficits and brain damage induced by moderate lateral fluid percussion injury in mice.

RATIONALE: There are evidences indicating the role of kinins in pathophysiology of traumatic brain injury, but little is known about their action on memory deficits. OBJECTIVES: Our aim was to establish the role of bradykinin receptors B1 (B1R) and B2 (B2R) on the behavioral, biochemical, and histologic features elicited by moderate lateral fluid percussion injury (mLFPI) in mice. METHODS: The role of kinin B1 and B2 receptors in brain damage, neuromotor, and cognitive deficits induced by mLFPI, was evaluated by means of subcutaneous injection of B2R antagonist (HOE-140; 1 or 10 nmol/kg) or B1R antagonist (des-Arg9-[Leu8]-bradykinin (DAL-Bk; 1 or 10 nmol/kg) 30 min and 24 h after brain injury. Brain damage was evaluated in the cortex, being considered as lesion volume, inflammatory, and oxidative damage. The open field and elevated plus maze tests were performed to exclude the nonspecific effects on object recognition memory test. RESULTS: Our data revealed that HOE-140 (10 nmol/kg) protected against memory impairment. This treatment attenuated the brain edema, interleukin-1ß, tumor necrosis factor-α, and nitric oxide metabolites content elicited by mLFPI. Accordingly, HOE-140 administration protected against the increase of nicotinamide adenine dinucleotide phosphate oxidase activity, thiobarbituric-acid-reactive species, protein carbonylation generation, and Na⁺ K⁺ ATPase inhibition induced by trauma. Histologic analysis showed that HOE-140 reduced lesion volume when analyzed 7 days after brain injury. CONCLUSIONS: This study suggests the involvement of the B2 receptor in memory deficits and brain damage caused by mLFPI in mice.

Exercise pre-conditioning reduces brain inflammation and protects against toxicity induced by traumatic brain injury: behavioral and neurochemical approach.

Although the favorable effects of physical exercise in neurorehabilitation after traumatic brain injury (TBI) are well known, detailed pathologic and functional alterations exerted by previous physical exercise on post-traumatic cerebral inflammation have been limited. In the present study, it is showed that fluid percussion brain injury (FPI) induced motor function impairment, followed by increased plasma fluorescein extravasation and cerebral inflammation characterized by interleukin-1ß, tumor necrosis factor-α (TNF-α) increase, and decreased IL-10. In addition, myeloperoxidase (MPO) increase and Na⁺,K⁺-ATPase activity inhibition after FPI suggest that the opening of blood-brain barrier (BBB) followed by neurtrophils infiltration and cerebral inflammation may contribute to the failure of selected targets leading to secondary damage. In fact, Pearson's correlation analysis revealed strong correlation of MPO activity increase with Na⁺,K⁺-ATPase activity inhibition in sedentary rats. Statistical analysis also revealed that previous running exercise (4 weeks) protected against FPI-induced motor function impairment and fluorescein extravasation. Previous physical training also induced IL-10 increase per se and protected against cerebral IL-1ß, and TNF-α increase and IL-10 decrease induced by FPI. This protocol of physical training was effective against MPO activity increase and Na⁺,K⁺-ATPase activity inhibition after FPI. The present protection correlated with MPO activity decrease suggests that the alteration of cerebral inflammatory status profile elicited by previous physical training reduces initial damage and limits long-term secondary degeneration after TBI. This prophylactic effect may facilitate functional recovery in patients suffering from brain injury induced by TBI.

Creatine reduces oxidative stress markers but does not protect against seizure susceptibility after severe traumatic brain injury.

Achievements made over the last years have highlighted the important role of creatine in health and disease. However, its effects on hyperexcitable circuit and oxidative damage induced by traumatic brain injury (TBI) are not well understood. In the present study we revealed that severe TBI elicited by fluid percussion brain injury induced oxidative damage characterized by protein carbonylation, thiobarbituric acid reactive species (TBARS) increase and Na(+),K(+)-ATPase activity inhibition 4 and 8 days after neuronal injury. Statistical analysis showed that after TBI creatine supplementation (300 mg/kg, p.o.) decreased the levels of protein carbonyl and TBARS but did not protect against TBI-induced Na(+),K(+)-ATPase activity inhibition. Electroencephalography (EEG) analysis revealed that the injection of a subconvulsant dose of PTZ (35 mg/kg, i.p.), 4 but not 8 days after neuronal injury, decreased latency for the first clonic seizures and increased the time of spent generalized tonic-clonic seizures compared with the sham group. In addition, creatine supplementation had no effect on convulsive parameters induced by a subconvulsant dose of PTZ. Current experiments provide evidence that lipid and protein oxidation represents a separate pathway in the early post-traumatic seizures susceptibility. Furthermore, the lack of consistent anticonvulsant effect exerted by creatine in this early phase suggests that its apparent antioxidant effect does not protect against excitatory input generation induced by TBI.

N-Acetylcysteine prevents baker's-yeast-induced inflammation and fever.

OBJECTIVE AND DESIGN: To investigate whether N-acetylcysteine (NAC) alters baker's-yeast-induced fever and inflammation. MATERIAL OR SUBJECTS: Male Wistar rats (26-28 days old) injected with baker's yeast (135 mg/kg, intraperitoneal) or prostaglandin E(2) (300 ng/100 µL, intrathecal). TREATMENT: Rats were injected with NAC (500 mg/kg, subcutaneous, or 50 µg/100 µL, intrathecal) 1 h before, or 2 h after, pyrogen injection. METHODS: Rectal temperature changes induced by baker's yeast, PGE(2) and NAC were followed up over time. Four hours after baker's yeast injection, total leukocytes, protein, interleukin (IL)-1ß, tumor necrosis factor (TNF)-α and nonprotein thiol content were assessed in peritoneal lavage and hypothalamus. RESULTS: Systemic administration of NAC decreased leukocytes, protein, IL-1ß and TNF-α levels in peritoneal lavage, and decreased IL-1ß levels in the hypothalamus. The central administration of NAC prevented baker's-yeast-induced fever, but did not alter the febrile response elicited by prostaglandin E(2). CONCLUSION: These results suggest an anti-inflammatory and antipyretic role for NAC in yeast-induced peritonitis.

Diacerein decreases TNF-alpha and IL-1beta levels in peritoneal fluid and prevents Baker's yeast-induced fever in young rats.

OBJECTIVE: To investigate the effect of diacerein, an anti-inflammatory drug, on body temperature and protocols of fever induction in male Wistar rats. METHODS: The effect of diacerein (5.0 mg/kg, s.c.) on rectal temperature (T (R)) changes induced by Baker's yeast (0.135 g/kg, i.p.) and PGE(2) (10 ng/animal, i.t.) was evaluated. T (R) changes were recorded over time. The leukocyte count and TNF-alpha and IL-1beta content were evaluated in the peritoneal fluid by means of optical microscopy and enzyme immunoassay (ELISA kits), respectively. RESULTS: The administration of diacerein to febrile animals attenuated Baker's yeast-induced fever but did not alter prostaglandin E(2)-induced fever. Diacerein prevented the development of Baker's yeast-induced fever and significantly attenuated the increase in peritoneal leukocytes and decreased IL-1beta and TNF-alpha levels in peritoneal fluid. CONCLUSIONS: These data suggest that diacerein partially protects against Baker's yeast-induced fever and peritoneal leukocyte migration, and indicate that this effect appears to be due to inhibition of release of cytokines (such as TNF-alpha and IL-1beta).