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The hippocampus is particularly vulnerable to traumatic brain injury (TBI), the consequences of which are manifested as learning and memory deficits. Following injury, substantive spontaneous cognitive recovery occurs, suggesting that innate repair mechanisms exist in the brain. However, the underlying mechanism contributing to this is largely unknown. The existence of neural stem cells in the adult hippocampal dentate gyrus (DG) and their proliferative response following injury led us to speculate that neurogenesis may contribute to cognitive recovery following TBI. To test this, we first examined the time course of cognitive recovery following lateral fluid percussion injury in rats. Cognitive deficits were tested at 11-15, 26-30 or 56-60 days post-injury using Morris Water Maze. At 11-15 and 26-30 days post-injury, animals displayed significant cognitive deficits, which were no longer apparent at 56-60 days post-TBI, suggesting an innate cognitive recovery at 56-60 days. We next examined the proliferative response, maturational fate and integration of newly generated cells in the DG following injury. Specifically, rats received BrdU at 2-5 days post-injury followed by Fluorogold (FG) injection into the CA3 region at 56 days post-TBI. We found the majority of BrdU+ cells which survived for 10 weeks became dentate granule neurons, as assessed by NeuN and calbindin labeling, approximately 30% being labeled with FG, demonstrating their integration into the hippocampus. Additionally, some BrdU+ cells were synaptophysin-positive, suggesting they received synaptic input. Collectively, our data demonstrate the extensive anatomical integration of new born dentate granule neurons at the time when innate cognitive recovery is observed.

Background: In previous studies, it has been shown that intravenous lactate therapy can improve brain neurochemistry, adenosine triphosphate (ATP) generation and outcome after traumatic brain injury (TBI) in rats. In this study, we examined: (1) four L-lactate concentrations to determine the optimal therapeutic dose post TBI in terms of cognitive function; (2) ATP production after TBI for the L-lactate concentration found to be the optimal dose; (3) the possible production of lactic acidosis with the highest L-lactate concentration tested., Methods: Thirty minutes following a fluid percussion injury (FPI) over the left cerebral hemisphere, the animals received an intravenous infusion of 10, 28, 100, or 280 mM L-lactate (n = 10 for each group) for 3 h at a rate of 0.65 ml/h. Shams and control injured animals received a saline infusion. At 11-15 days post injury, cognitive deficits were examined using the Morris Water Maze (MWM) test. Three groups of rats were used for ATP analysis: shams, injured + saline infusion, and injury + the optimal lactate dose as determined by the MWM (n = 4/group). Additionally, a group receiving 280 mM L-lactate (n = 5) and one receiving a saline infusion (n = 3) were monitored for arterial blood variables and blood pressures., Findings: In the MWM test, only the 100 mM L-lactate-treated injured animals showed a significant reduction in cognitive deficits when compared to saline-treated injured animals (p

Evidence of injury-induced neurogenesis in the adult hippocampus suggests that an endogenous repair mechanism exists for cognitive dysfunction following traumatic brain injury (TBI). One factor that may be associated with this restoration is S100B, a neurotrophic/mitogenic protein produced by astrocytes, which has been shown to improve memory function. Therefore, we examined whether an intraventricular S100B infusion enhances neurogenesis within the hippocampus following experimental TBI and whether the biological response can be associated with a measurable cognitive improvement. Following lateral fluid percussion or sham injury in male rats (n = 60), we infused S100B (50 ng/h) or vehicle into the lateral ventricle for 7 days using an osmotic micro-pump. Cell proliferation was assessed by injecting the mitotic marker bromodeoxyuridine (BrdU) on day 2 postinjury. Quantification of BrdU-immunoreactive cells in the dentate gyrus revealed an S100B-enhanced proliferation as assessed on day 5 post-injury (p < 0.05), persisting up to 5 weeks (p < 0.05). Using cell-specific markers, we determined the relative numbers of these progenitor cells that became neurons or glia and found that S100B profoundly increased hippocampal neurogenesis 5 weeks after TBI (p < 0.05). Furthermore, spatial learning ability, as assessed by the Morris water maze on day 30-34 post-injury, revealed an improved cognitive performance after S100B infusion (p < 0.05). Collectively, our findings indicate that an intraventricular S100B infusion induces neurogenesis within the hippocampus, which can be associated with an enhanced cognitive function following experimental TBI. These observations provide compelling evidence for the therapeutic potential of S100B in improving functional recovery following TBI.

It is well known that the cognitive functions of juveniles recover to a greater extent than adult patients following traumatic brain injury (TBI). The exact mechanisms underlying this age-related disparity are unknown; however, we speculate that this improved recovery in juveniles following TBI may be associated with an endogenous neurogenic response in the hippocampus. We, therefore, examined the effects of TBI on cellular proliferation and differentiation in the dentate gyrus (DG) of the hippocampus in juvenile and adult rats following lateral fluid percussion injury (FPI). The temporal profile of the injury-induced proliferative response was determined using BrdU labeling at varying survival times. The differentiation of these newly generated cells was investigated using cell-type specific markers. We found that, following injury, there was a significant increase in cell proliferation in the DG in both injured juveniles and adults at 2 days post injury when compared to shams. When comparing the extent of cell proliferation between juveniles and adults following TBI, the absolute number of cells generated in the subgranular zone (SGZ) was far greater in the juveniles. Moreover, the percentage of newly generated cells in the SGZ that differentiated into neurons was nearly two times higher in the juveniles as compared to adults. Conversely, more glial differentiation was observed in the DG of adult rats. These findings provide compelling evidence that age-related differences in the neurogenic response to injury may underlie the differences observed in cognitive recovery in juvenile mammals as compared to adults following TBI.

Elevated serum S100B levels have been shown to be a predictor of poor outcome after traumatic brain injury (TBI). Experimental data, on the other hand, demonstrate a neuroprotective and neurotrophic effect of this calcium-binding protein. The purpose of this study was to examine the role of increased S100B levels on functional outcome after TBI. Following lateral fluid percussion or sham injury in male Sprague Dawley rats (n = 56), we infused S100B (50 ng/h) or vehicle into the cerebrospinal fluid of the ipsilateral ventricle for 7 days using an osmotic mini-pump. Assessment of cognitive performance by the Morris water maze on days 30-34 after injury revealed an improved performance of injured animals after S100B infusion (p < 0.05), when compared to vehicle infusion. Blood samples for analysis of clinical markers of brain damage, S100B and neuron specific enolase, taken at 30 min, 3 h, 4 h, 2 days, or 5 days showed a typical peak 3 h after injury (p < 0.01), and higher serum levels correlated significantly with an impaired cognitive recovery (p < 0.01). The correlation of higher serum S100B levels with poor water maze performance may result from injury induced opening of the blood-brain barrier, allowing the passage of S100B into serum. Thus while higher serum levels of S100B seem to reflect the degree of blood-brain barrier opening and severity of injury, a beneficial effect of intraventricular S100B administration on long-term functional recovery after TBI has been demonstrated for the first time. The exact mechanism by which S100B exerts its neuroprotective or neurotrophic influence remains unknown and needs to be elucidated by further investigation.

Background: Despite the high risk of venous thromboembolic events (VTE) in neuro-surgical patients, heparin prophylaxis has not been routinely established due to concern about bleeding complications. After initiating early low molecular weight heparin (LMWH) prophylaxis, we reviewed our patients in order to examine the viability of this practice., Method: Over a 3 year period, the records of patients admitted for elective neuro-surgery (ES), head injury (HI) or spontaneous intracranial haemorrhage (ICH) were analysed. Prophylaxis was performed with certoparin (3000 U anti-factor Xa s.c.) on the evening before ES and within 24 hours after surgery or admission whenever a CT did not show a progressive haematoma. Contraindications for LMWH were prothrombin time <70%, partial thrombo-plastin time >40 s, platelet count <100.000/ml, and platelet aggregation test sum <60%. The incidence of bleeding complications, VTE, and resulting morbidity/mortality was assessed., Findings: 294 patients were admitted for ES, 344 for HI, and 302 for ICH. 155 of these were excluded because of contraindications. Intracranial bleeding was recorded in 1.5% (ES 1.1%, HI 3.5%, ICH 0%) and operative revision was performed in 1.1% (ES 0.7%, HI 2.8%) of patients. One case of moderate disability and no mortality occurred. The incidence of VTE and pulmonary embolism was documented in 0.2% and 0.1% of patients, with no associated mortality. No heparin induced thrombocytopenia was observed., Interpretation: In neurosurgical patients, antithrombotic prophylaxis with certoparin was determined to be safe and efficacious when contraindications are carefully considered and a 12-hour time interval before and after surgery was guaranteed. This retrospective analysis should encourage a prospective trial of early LMWH prophylaxis.

Recent studies have identified endogenous neural stem cells in adult rodent brains. The present study characterizes the early response of mitotically active cells in the brain to traumatic brain injury. Animals were subjected to lateral fluid percussion injury and sacrificed at various times after injury. To examine increases in cell proliferation animals were injected with the mitotic marker bromodeoxyuridine (BrdU) 24 h before sacrifice. Increased numbers of mitotically active cells were observed at 2 days in the subgranular zone (SGZ) and the subependymal zone (SEZ) under the injury site. To characterize the differentiation potential of these cells, animals were injected with BrdU 18 and 20 h after injury, then sacrificed at multiple time points after injury. Histologically, co-localization with betaIII-tubulin (neuronal marker) and BrdU was evident at 10 and 15 days postinjury in the SGZ. Flow cytometry analysis was used to quantitatively assess neurogenesis in the SEZ. Animals were sacrificed 1, 5, or 10 days after injury and tissue sections extracted, grown in tissue culture for 24 h, fixed, and stained for nestin and betaIII-tubulin to identify newly formed neurons. The percentage of cells expressing both markers was determined using flow cytometry analysis. There was a significant increase in newly differentiated neurons by 10 days postinjury in the SEZ. Thus, we conclude that traumatic brain injury stimulates an increase in proliferation of endogenous neural stem/progenitor cells and that a significant number of these express a neuronal marker. This response may be the brain's way of trying to heal itself after injury.