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1.
Neuroscience ; 148(2): 359-70, 2007 Aug 24.
Article in English | MEDLINE | ID: mdl-17681695

ABSTRACT

Traumatic brain injury (TBI) causes selective hippocampal cell death which is believed to be associated with the cognitive impairment observed in both clinical and experimental settings. The endogenous neurotrophin-4/5 (NT-4/5), a TrkB ligand, has been shown to be neuroprotective for vulnerable CA3 pyramidal neurons after experimental brain injury. In this study, infusion of recombinant NT-4/5 increased survival of CA2/3 pyramidal neurons to 71% after lateral fluid percussion brain injury in rats, compared with 55% in vehicle-treated controls. The functional outcome of this NT-4/5-mediated neuroprotection was examined using three hippocampal-dependent behavioral tests. Injury-induced impairment was evident in all three tests, but interestingly, there was no treatment-related improvement in any of these measures. Similarly, injury-induced decreased excitability in the Schaffer collaterals was not affected by NT-4/5 treatment. We propose that a deeper understanding of the factors that link neuronal survival to recovery of function will be important for future studies of potentially therapeutic agents.


Subject(s)
Brain Injuries/drug therapy , Hippocampus/pathology , Nerve Growth Factors/therapeutic use , Neurons/drug effects , Neuroprotective Agents/therapeutic use , Animals , Association Learning/drug effects , Behavior, Animal/drug effects , Brain Injuries/pathology , Cell Count/methods , Disease Models, Animal , Dose-Response Relationship, Radiation , Electric Stimulation/methods , Evoked Potentials/drug effects , Evoked Potentials/radiation effects , Hippocampus/physiopathology , In Vitro Techniques , Male , Motor Activity/drug effects , Neurons/physiology , Rats , Rats, Sprague-Dawley , Recovery of Function/drug effects , Recovery of Function/physiology , Time Factors
2.
Eur J Neurosci ; 23(5): 1089-102, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16553773

ABSTRACT

Traumatic brain injury (TBI) causes selective hippocampal cell death, which is believed to be associated with cognitive impairment observed both in clinical and experimental settings. Although neurotrophin administration has been tested as a strategy to prevent cell death following TBI, the potential neuroprotective role of neurotrophin-4/5 (NT-4/5) in TBI remains unknown. We hypothesized that NT-4/5 would offer neuroprotection for selectively vulnerable hippocampal neurons following TBI. Measurements of NT-4/5 in rats subjected to lateral fluid percussion (LFP) TBI revealed two-threefold increases in the injured cortex and hippocampus in the acute period (1-3 days) following brain injury. Subsequently, the response of NT-4/5 knockout (NT-4/5(-/-)) mice to controlled-cortical impact TBI was investigated. NT-4/5(-/-) mice were more susceptible to selective pyramidal cell loss in Ahmon's corn (CA) subfields of the hippocampus following TBI, and showed impaired motor recovery when compared with their brain-injured wild-type controls (NT-4/5(wt)). Additionally, we show that acute, prolonged administration of recombinant NT-4/5 (5 microg/kg/day) prevented up to 50% of the hippocampal CA pyramidal cell death following LFP TBI in rats. These results suggest that post-traumatic increases in endogenous NT-4/5 may be part of an adaptive neuroprotective response in the injured brain, and that administration of this neurotrophic factor may be useful as a therapeutic strategy following TBI.


Subject(s)
Brain Injuries , Hippocampus , Nerve Growth Factors/metabolism , Neuroprotective Agents/metabolism , Pyramidal Cells/metabolism , Animals , Brain Injuries/metabolism , Brain Injuries/pathology , Gene Deletion , Hippocampus/cytology , Hippocampus/metabolism , Hippocampus/pathology , Humans , Male , Mice , Mice, Knockout , Nerve Growth Factors/administration & dosage , Nerve Growth Factors/genetics , Neuroprotective Agents/administration & dosage , Pyramidal Cells/cytology , Pyramidal Cells/pathology , Random Allocation , Rats
3.
Nitric Oxide ; 12(2): 61-9, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15740979

ABSTRACT

There are conflicting data regarding the role of nitric oxide (NO) produced by inducible NO synthase (iNOS) in the pathophysiology of traumatic brain injury (TBI). In this report, we evaluated the effect of a potent selective (iNOS) inhibitor, 1400W, on histopathological outcome following TBI in a rat model of lateral fluid percussion brain injury. First, to design an appropriate treatment protocol, the parallel time courses of iNOS and neuronal NOS (nNOS) gene expression, protein synthesis, and activity were investigated. Early induction of iNOS gene was observed in the cortex of injured rats, from 6 to 72 h with a peak at 24 h. Similarly, iNOS protein was detected from 24 to 72 h and de novo synthesized iNOS was functionally active, as measured by Ca2+-independent NOS activity. The kinetic studies of nNOS showed discrepancies, since nNOS gene expression and protein synthesis were constant in the cortex of injured rats from 24 to 72 h, while Ca2+-dependent constitutive NOS activity was markedly decreased at 24 h, persisting up to 72 h. Second, treatment with 1400W, started as a bolus of 20 mg kg-1 (s.c.) at 18 h post-TBI, followed by s.c.-infusion at a rate of 2.2 mg kg-1 h-1 between 18 and 72 h, reduced by 64% the brain lesion volume at 72 h. However, the same treatment paradigm initiated 24 h post-TBI did not have any effect. In conclusion, administration of a selective iNOS inhibitor, 1400W, even delayed by 18 h improves histopathological outcome supporting a detrimental role for iNOS induction after TBI.


Subject(s)
Amidines/therapeutic use , Benzylamines/therapeutic use , Brain Injuries/drug therapy , Brain Injuries/pathology , Enzyme Inhibitors/therapeutic use , Nitric Oxide Synthase/antagonists & inhibitors , Amidines/pharmacology , Animals , Benzylamines/pharmacology , Brain Injuries/enzymology , Calcium/metabolism , Disease Models, Animal , Enzyme Inhibitors/pharmacology , Male , Nerve Tissue Proteins/biosynthesis , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neurons/enzymology , Nitric Oxide Synthase/biosynthesis , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type I , Nitric Oxide Synthase Type II , Rats , Rats, Sprague-Dawley , Time Factors
4.
Curr Opin Pharmacol ; 3(1): 27-32, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12550738

ABSTRACT

The intensity of experimental and clinical research to identify a neuroprotective drug for the treatment of traumatic brain injury is motivated by the devastating morbidity and mortality of this condition. Encouraging experimental work has led so far to disappointing clinical trials and the identification of new potential therapeutic targets is critically dependent on a better understanding of the chronic pathophysiology triggered by the initial insult. Future advances in the pharmacological treatment of traumatic brain injury are likely to include the evaluation of sequentially timed therapies combining multiple and targeted agents, and manipulation of the newly discovered neurogenic potential of the adult brain together with the refinement of traditional interventions to block specific cytotoxic cascades.


Subject(s)
Brain Injuries/drug therapy , Brain Injuries/metabolism , Animals , Brain Injuries/physiopathology , Cannabinoids/therapeutic use , Enzyme Inhibitors/therapeutic use , Excitatory Amino Acid Antagonists/therapeutic use , Glutamic Acid/metabolism , Humans
5.
Neuroreport ; 10(6): 1363-7, 1999 Apr 26.
Article in English | MEDLINE | ID: mdl-10363954

ABSTRACT

The aim of our study was to assess polymorphonuclear neutrophil infiltration into the injured parenchyma after a traumatic brain injury (TBI). Myeloperoxidase (MPO) activity was assayed on the hippocampus, temporal and parietal cortex 6, 24, 48, 72, and 120 h post-trauma. MPO activity occurred in these structures from 6 h post-trauma and was maximum at 24-48 h. It was resolved by 72 h in the hippocampus and the parietal cortex, but persisted in the temporal cortex until 120 h after trauma. This suggests that neutrophil infiltration is a delayed phenomenon in the physiopathology of TBI. Considering that a large therapeutic window may be crucial in the management of TBI, inhibition of neutrophil infiltration needs to be further investigated following cerebral trauma.


Subject(s)
Brain Injuries/physiopathology , Hippocampus/physiopathology , Neutrophils/physiology , Parietal Lobe/physiopathology , Peroxidase/metabolism , Temporal Lobe/physiopathology , Animals , Brain Injuries/pathology , Functional Laterality , Hippocampus/pathology , Kinetics , Male , Parietal Lobe/pathology , Percussion , Rats , Rats, Sprague-Dawley , Temporal Lobe/pathology , Time Factors
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