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.

The effect of NADPH-oxidase inhibitor apocynin on cognitive impairment induced by moderate lateral fluid percussion injury: role of inflammatory and oxidative brain damage.

Traumatic brain injury (TBI) is a devastating disease that commonly causes persistent mental disturbances and cognitive deficits. Although studies have indicated that overproduction of free radicals, especially superoxide (O2(-)) derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is a common underlying mechanism of pathophysiology of TBI, little information is available regarding the role of apocynin, an NADPH oxidase inhibitor, in neurological consequences of TBI. Therefore, the present study evaluated the therapeutic potential of apocynin for treatment of inflammatory and oxidative damage, in addition to determining its action on neuromotor and memory impairments caused by moderate fluid percussion injury in mice (mLFPI). Statistical analysis revealed that apocynin (5mg/kg), when injected subcutaneously (s.c.) 30min and 24h after injury, had no effect on neuromotor deficit and brain edema, however it provided protection against mLFPI-induced object recognition memory impairment 7days after neuronal injury. The same treatment protected against mLFPI-induced IL-1ß, TNF-α, nitric oxide metabolite content (NOx) 3 and 24h after neuronal injury. Moreover, apocynin treatment reduced oxidative damage (protein carbonyl, lipoperoxidation) and was effective against mLFPI-induced Na(+), K(+)-ATPase activity inhibition. The present results were accompanied by effective reduction in lesion volume when analyzed 7days after neuronal injury. These data suggest that superoxide (O2(-)) derived from NADPH oxidase can contribute significantly to cognitive impairment, and that the post injury treatment with specific NADPH oxidase inhibitors, such as apocynin, may provide a new therapeutic approach to the control of neurological disabilities induced by TBI.

Antioxidant activity elicited by low dose of caffeine attenuates pentylenetetrazol-induced seizures and oxidative damage in rats.

Although caffeine supplementation has a beneficial effect on people with neurological disorders, its implications for oxidative damage related to seizures are not well documented. Thus the aim of this study was to investigate the effects of two weeks caffeine supplementation (6mg/kg; p.o.) on seizures and neurochemical alterations induced by pentylenetetrazol (PTZ 60mg/kg i.p.). Statistical analyses showed that long-term rather than single dose caffeine administration decreased the duration of PTZ-induced seizures in adult male Wistar rats as recorded by cortical electroencephalographic (EEG) and behavioral analysis. The quantification of EEG recordings also revealed that caffeine supplementation protected against a wave increase induced by PTZ. Neurochemical analyses revealed that caffeine supplementation increased glutathione (GSH) content per se and protected against the increase in the levels of thiobarbituric acid reactive substances (TBARS) and oxidized diclorofluoresceine diacetate (DCFH-DA). Also, caffeine prevent the decrease in GSH content and Na(+), K(+)-ATPase activity induced by PTZ. Our data also showed that the infusion of L-buthionine sulfoximine (BSO; 3.2µmol/site i.c.v), an inhibitor of GSH synthesis, two days before injecting PTZ reversed the anticonvulsant effect caused by caffeine. BSO infusion also decreased GSH content and Na(+), K(+)-ATPase activity. However, it increased DCFH-DA oxidation and TBARS per se and reversed the protective effect of caffeine. Results presented in this paper support the neuroprotective effects of low long-term caffeine exposure to epileptic damage and suggest that the increase in the cerebral GSH content caused by caffeine supplementation may provide a new therapeutic approach to the control of seizure.

Treadmill exercise protects against pentylenetetrazol-induced seizures and oxidative stress after traumatic brain injury.

Traumatic brain injury (TBI) is a major cause of acquired epilepsy, and significant resources are required to develop a better understanding of the pathologic mechanism as targets for potential therapies. Thus, we decided to investigate whether physical exercise after fluid percussion injury (FPI) protects from oxidative and neurochemical alterations as well as from behavioral electroencephalographic (EEG) seizures induced by subeffective convulsive doses of pentylenetetrazol (PTZ; 35 mg/kg). Behavioral and EEG recordings revealed that treadmill physical training increased latency to first clonic and tonic-clonic seizures, attenuated the duration of generalized seizures, and protected against the increase of PTZ-induced Racine scale 5 weeks after neuronal injury. EEG recordings also revealed that physical exercise prevented PTZ-induced amplitude increase in TBI animals. Neurochemical analysis showed that exercise training increased glutathione/oxidized glutathione ratio and glutathione levels per se. Exercise training was also effective against alterations in the redox status, herein characterized by lipid peroxidation (thiobarbituric acid reactive substances), protein carbonyl increase, as well as the inhibition of superoxide dismutase and Na⁺,K⁺-ATPase activities after FPI. On the other hand, histologic analysis with hematoxylin and eosin revealed that FPI induced moderate neuronal damage in cerebral cortex 4 weeks after injury and that physical exercise did not protect against neuronal injury. These data suggest that the ability of physical exercise to reduce FPI-induced seizures is not related to its protection against neuronal damage; however, the effective protection of selected targets, such as Na⁺/K⁺-ATPase elicited by physical exercise, may represent a new line of treatment for post-traumatic seizure susceptibility.

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.