[Show abstract][Hide abstract] ABSTRACT: Animal models are necessary to elucidate changes occurring after brain injury and to establish new therapeutic strategies towards a stage where drug efficacy in brain injured patients (against all classes of symptoms) can be predicted. In this review, six established animal models of head trauma, namely fluid percussion, rigid indentation, inertial acceleration, impact acceleration, weight-drop and dynamic cortical deformation are evaluated. While no single animal model is entirely successful in reproducing the complete spectrum of pathological changes observed after injury, the validity of these animal models including face, construct, etiological and construct validity and how the models constitute theories about brain injury is addressed. The various types of injury including contact (direct impact) and non-contact (acceleration/deceleration) and their associated pathologies are described. The neuropathologic classifications of brain injury including primary and secondary, focal and diffuse are discussed. Animal models and their compatibility with microdialysis studies are summarised particularly regarding the role of excitatory and inhibitory amino acid neurotransmitters. This review concludes that the study of neurotransmitter interactions within and between brain regions can facilitate the development of novel compounds targeted to treat those cognitive deficits not limited to a single pharmacological class and may be useful in the investigation of new therapeutic strategies and pharmacological testing for improved treatment for traumatic head injury.
[Show abstract][Hide abstract] ABSTRACT: Dysfunction of the gastrointestinal tract is a common occurrence after traumatic brain injury (TBI). We hypothesized that increased intestinal permeability may result from a precisely controlled percussion injury to the exposed brains of anesthetized rats and that such an effect could be assessed in vitro using excised intestinal mucosae mounted in Ussing chambers.
After craniotomy over the left medial prefrontal cortex on anesthetized rats, neurotrauma was produced using a pneumatically driven impactor on the exposed brain. Control rats were subjected to identical procedures but did not receive an impact. Muscle-stripped rat intestinal ileal and colonic segments were mounted in Ussing chambers within 30 minutes of death. Transepithelial electrical resistance (TEER) and the apparent permeability coefficient (Papp) of [C]-mannitol were recorded from intestinal tissue for 120 minutes. Histopathologic analysis was also performed to determine any gross morphologic changes in the intestine.
Ileal and colonic mucosae showed no differences in TEER in ileum or colon of TBI rats compared with controls. The Papp of mannitol was significantly increased in ilea from rats previously exposed to TBI compared with controls. Histologic analysis showed gross changes to 50% of the ileal but not the colonic sections from TBI rats.
TBI results in significantly reduced ileal barrier function, most likely mediated by open tight junctions. For patients with acute head injury, this may have implications for subsequent oral absorption of nutrients. Systemic delivery of luminal endotoxins may contribute to multiple organ failure.
The Journal of trauma 02/2008; 64(1):131-7; discussion 137-8. DOI:10.1097/TA.0b013e3181568d9f · 2.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Traumatic brain injury (TBI) produces a rapid and excessive elevation in extracellular glutamate that induces excitotoxic brain cell death. The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) is reported to suppress neurotransmitter release through selective activation of presynaptic group II metabotropic glutamate receptors. Therefore, strategies to elevate levels of NAAG following brain injury could reduce excessive glutamate release associated with TBI. We hypothesized that the NAAG peptidase inhibitor, ZJ-43 would elevate extracellular NAAG levels and reduce extracellular levels of amino acid neurotransmitters following TBI by a group II metabotropic glutamate receptor (mGluR)-mediated mechanism. Dialysate levels of NAAG, glutamate, aspartate and GABA from the dorsal hippocampus were elevated after TBI as measured by in vivo microdialysis. Dialysate levels of NAAG were higher and remained elevated in the ZJ-43 treated group (50 mg/kg, i.p.) compared with control. ZJ-43 treatment also reduced the rise of dialysate glutamate, aspartate, and GABA levels. Co-administration of the group II mGluR antagonist, LY341495 (1 mg/kg, i.p.) partially blocked the effects of ZJ-43 on dialysate glutamate and GABA, suggesting that NAAG effects are mediated through mGluR activation. The results are consistent with the hypothesis that inhibition of NAAG peptidase may reduce excitotoxic events associated with TBI.
Journal of Neurochemistry 06/2006; 97(4):1015-25. DOI:10.1111/j.1471-4159.2006.03786.x · 4.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study describes a microdialysis model that investigates the biochemical response of the brain to non-fatal impact trauma.
A controlled cortical impact (mild and severe) was performed to the left medial prefrontal cortex (mPfc) in the isoflurane-anaesthesised
rat. This was followed by intracerebral microdialysis whereby a microdialysis probe was implanted into the site of the injury.
Changes in dialysate glutamate, aspartate and GABA levels were investigated immediately (i.e. 25 min) and 265 min following a local mild and severe impact to the brain. In addition, the effect of local perfusion with
a depolarizing concentration of KCl (100 mM, 20 min) was also investigated 165 min after impact.
Dialysate levels measured 25 min after impact (n=14) showed an impactdependent increase in glutamate (6 and 8-fold), aspartate
(4 and 5-fold) and GABA (3 and 6-fold) following mild and severe impact respectively compared to non-impact controls. Dialysate
levels measured 265 min after mild (n=12) and severe (n=13) impact had stabilized and continued to show a local 5-fold (mild)
and 4-fold (severe) increase in local glutamate, a 6-fold (mild) and 3-fold (severe) increase in aspartate and a (3-fold (mild)
and 5-fold (severe)) increase in GABA levels compared to control. Intra-mPfc KCl (n=14) increased local dialysate glutamate
levels (4-fold following mild impact and 3-fold following severe impact) and aspartate levels (2-fold after both mild and
severe impact) while GABA levels did not differ from non-impacted controls following either a mild or severe impact.
The present findings show that microdialysis in intact brain can be combined with the controlled cortical impact model to
reveal selective impact-dependent and prolonged increases in local dialysate amino acid neurotransmitter levels. Furthermore,
we reveal that 165 min following either a mild or severe impact to the left mPfc KCl-stimulated glutamate and aspartate release
is abnormally increased while GABA release is not different compared to non-impacted controls. This finding may in part explain
the excitotoxicity that contributes to diffuse posttraumatic lesions associated with secondary injury.
[Show abstract][Hide abstract] ABSTRACT: This study investigates the involvement of capacitative Ca2+ entry in excitation-contraction coupling in guinea pig gallbladder smooth muscle. Thapsigargin (0.1 nM-1 microM, a sarcoplasmic reticulum Ca(2+)-ATPase inhibitor) produced slowly developing sustained tonic contractions in guinea pig isolated gallbladder strips. All contractions approached 50% of the response to carbachol (10 microM) after 55 min. Contractile responses to thapsigargin (1 microM) were abolished in a Ca(2+)-free medium. Subsequent re-addition of Ca2+ (2.5 mM) produced a sustained tonic contraction (99 +/- 6% of the carbachol response). The contractile response to Ca2+ re-addition following incubation of tissues in a Ca(2+)-free bathing solution in the absence of thapsigargin was significantly less than in its presence (79 +/- 4 % vs 100 +/- 7 % of carbachol; p < 0.05). Contractile responses to Ca2+ re-addition following treatment with thapsigargin were attenuated by (a) the L-type voltage-operated Ca2+ channel antagonist, nifedipine (10 microM) and (b) the general inhibitor of Ca2+ entry channels including store-operated channels, SK&F96365 (50 microM and 100 microM). In separate experiments, responses to Ca2+ re-addition were essentially abolished by the tyrosine kinase inhibitor, genistein (100 microM). These results suggest that capacitative Ca2+ entry provides a source of activator Ca2+ for guinea pig gallbladder smooth muscle contraction. Contractile responses to Ca2+ re-addition following depletion of sarcoplasmic reticulum Ca2+ stores with thapsigargin, are mediated in part by Ca2+ entry through voltage-operated Ca2+ channels and by capacitative Ca2+ entry through store-operated Ca2+ channels which can be blocked by SK&F96365. Furthermore, capacitative Ca2+ entry in this tissue may be modulated by tyrosine kinase.
Life Sciences 02/2004; 74(13):1659-69. DOI:10.1016/j.lfs.2003.08.030 · 2.70 Impact Factor