脑损伤后N-乙酰天冬氨酰谷氨酸肽酶抑制的神经保护

目的 探索颅脑损伤后N-乙酰天冬氨酰谷氨酸(NAAG)肽酶抑制的神经保护效应.方法 将20只SD大鼠随机分成4组后制作中度液压颅脑损伤模型.伤后3个时间点(即时,8 h,16 h)分别经腹腔注射新型NAAG肽酶抑制剂ZJ-43(各组剂量:0,50,100,150 mg/kg).伤后24 h处死动物取脑组织行Fluoro-Jade B组织荧光染色以及GFAP免疫组化染色.通过立体细胞计数着重观察大鼠海马CA2/3区退变神经元及正常胶质细胞的数量变化.结果 ZJ-43能显著减少颅脑损伤后的神经元退变(P＜0.01),其中小剂量处理组(50 mg/kg)保护作用最佳,还能同时显著减少儋颅脑损伤后的胶质细胞丢失(P＜0.05).结论 阻断NAAG肽酶活性能有效放大内源性递质NAAG的神经保护作用,从而阻断谷氨酸兴奋毒性的病理进程,有望成为治疗颅脑损伤的新策略.     

Immunomorphological sequelae of severe brain injury induced by fluid-percussion in juvenile pigs--effects of mild hypothermia

Severe traumatic brain injury (TBI) often leads to a bad outcome with considerable neurological deficits. Secondary brain injuries due to a rise of intracranial pressure (ICP) and global hypoxia-ischemia are critical and may be reduced in extent by mild hypothermia. A porcine animal model was used to study the effect of severe TBI, induced by fluid percussion (FP; 3.5+/-0.3 atm) in combination with a secondary insult, i.e., temporary blood loss with hypovolemic hypotension. Six-week-old juvenile pigs were subjected to this kind of severe TBI; one group was then submitted to moderate hypothermia at 32 degrees C for 6 h, starting 1 h after brain injury. Animals were killed after 24 h. TBI and hypothermia-associated alterations in the brains were investigated by immunohistochemistry with antibodies against microtubule-associated protein 2 (MAP-2) and beta-amyloid precursor protein (betaAPP). In addition, DNA fragmentation was investigated by the terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) method. Seven of the 13 normothermic TBI animals developed a secondary increase in ICP (TBI-NT-ICP) after an interval of several hours. None of the animals in the hypothermic trauma (TBI-HT) group exhibited a secondary ICP increase, indicating a protective effect of the treatment. TBI-HT animals showed significantly higher levels of MAP-2 immunoreactivity, lower levels of betaAPP immunoreactivity and less DNA fragmentation than the TBI-NT-ICP animals. Differences between the TBI-HT group and normothermic animals without an ICP increase (TBI-NT) were less marked. A considerable decrease in MAP-2 outside the site of TBI-FP administration was seen only in the TBI-NT-ICP animals. MAP-2 immunohistochemistry was thus a reliable marker of diffuse brain damage. Axonal injury was present in all TBI groups, indicating its special significance in neurotrauma. Thus, severe TBI caused by FP, combined with temporary blood loss, consistently produced traumatic axonal injury and focal brain damage. Mild hypothermia was able to prevent a secondary increase in ICP and its sequelae of diffuse hypoxic-ischemic brain injury. However, hypothermia did not afford protection from traumatic axonal injury.     

Combinational therapy using hypothermia and the immunophilin ligand FK506 to target altered pial arteriolar reactivity,axonal damage,and blood–brain barrier dysfunction after traumatic brain injury in rat

This study evaluated the utility of combinational therapy, coupling delayed posttraumatic hypothermia with delayed FK506 administration, on altered cerebral vascular reactivity, axonal injury, and blood–brain barrier (BBB) disruption seen following traumatic brain injury (TBI). Animals were injured, subjected to various combinations of hypothermic/FK506 intervention, and equipped with cranial windows to assess pial vascular reactivity to acetylcholine. Animals were then processed with antibodies to the amyloid precursor protein and immunoglobulin G to assess axonal injury and BBB disruption, respectively. Animals were assigned to five groups: (1) sham injury plus delayed FK506, (2) TBI, (3) TBI plus delayed hypothermia, (4) TBI plus delayed FK506, and (5) TBI plus delayed hypothermia with FK506. Sham injury plus FK506 had no impact on vascular reactivity, axonal injury, or BBB disruption. Traumatic brain injury induced dramatic axonal injury and altered pial vascular reactivity, while triggering local BBB disruption. Delayed hypothermia or FK506 after TBI provided limited protection. However, TBI with combinational therapy achieved significantly enhanced vascular and axonal protection, with no BBB protection. This study shows the benefits of combinational therapy, using posttraumatic hypothermia with FK506 to attenuate important features of TBI. This suggests that hypothermia not only protects but also extends the therapeutic window for improved FK506 efficacy.     

Polyethylene glycol treatment after traumatic brain injury reduces beta-amyloid precursor protein accumulation in degenerating axons

Polyethylene glycol (PEG; 2,000 MW; 30% v/v) is a nontoxic molecule that can be injected intravenously and possesses well-documented neuroprotective properties in the spinal cord of the guinea pig. Recent studies have shown that intravenous PEG can also enter the rat brain parenchyma after injury and repair cellular membrane damage in the region of the corpus callosum. Disrupted anterograde axonal transport and resulting beta-amyloid precursor protein (APP) accumulation are byproducts of traumatic axonal injury (TAI) in the brain. APP accumulation indicates axonal degeneration as a result of axotomy, a detriment that can lead to cell death. In this study, we show that PEG treatment can eliminate APP accumulation in specific brain areas of rats receiving TAI. Six areas of the brain were analyzed: the medial cortex, hippocampus, lateral cortex, thalamus, medial lemniscus, and medial longitudinal fasciculus. Increased APP expression after injury was abolished in the thalamus and reduced in the medial longitudinal fasciculus by PEG treatment. In all remaining areas except for the lateral cortex, APP expression was not increased between injured and uninjured brains, indicating that damage was undetected in those brain areas in this study.     

The role of mitochondrial transition pore, and its modulation, in traumatic brain injury and delayed neurodegeneration after TBI

Following severe traumatic brain injury (TBI), a complex interplay of pathomechanism, such as exitotoxicity, oxidative stress, inflammatory events, and mitochondrial dysfunction occurs. This leads to a cascade of neuronal and axonal pathologies, which ultimately lead to axonal failure, neuronal energy metabolic failure, and neuronal death, which in turn determine patient outcome. For mild and moderate TBI, the pathomechanism is similar but much less frequent and ischemic cell death is unusual, except with mass lesions. Involvement of mitochondria in acute post-traumatic neurodegeneration has been extensively studied during the last decade, and there are a number of investigations implicating the activation of the mitochondrial permeability transition pore (mPTP) as a “critical switch” which determines cell survival after TBI. Opening of the mPTP is modulated by several factors occurring after a severe brain injury. Modern neuroprotective strategies for prevention of the neuropathological squeal of traumatic brain injury have now begun to address the issue of mitochondrial dysfunction, and drugs that protect mitochondrial viability and prevent apoptotic cascade induced by mPTP opening are about to begin phase II and III clinical trials. Cyclosporin A, which has been reported to block the opening of mPTP, showed a significant decrease in mitochondrial damage and intra-axonal cytoskeletal destruction thereby protecting the axonal shaft and blunting axotomy. This review addresses an important issue of mPT activation after severe head injury, its role in acute post-traumatic neurodegeneration, and the rationale for targeting the mPTP in experimental and clinical TBI studies.     

乌司他丁预处理对小鼠颅脑损伤保护的初步研究

目的探讨乌司他丁(UTI)预处理对小鼠颅脑损伤早期的保护作用。方法 BALB/c小鼠44只,随机分为假手术组(SO组)、创伤性脑损伤组(TBI组)、乌司他丁预处理组(UTI组)和生理盐水对照组(Control组)。预处理组连续3 d给予UTI 300 000 U/(kg.d)腹腔注射。除SO组外,其余各组应用自由落体打击法建立创伤性脑损伤模型。采用干湿重法检测脑组织含水量,HE染色光镜下观察损伤皮质区形态变化,使用Western blot方法检测脑组织中水通道蛋白4(AQP4)表达。结果 UTI组颅脑损伤早期(24 h)脑组织含水量低于TBI组(P<0.05),其损伤皮质区神经元状态优于TBI组。同时,UTI组的AQP4蛋白表达水平低于TBI组,差异显著(P<0.05)。结论乌司他丁预处理减轻颅脑损伤早期脑水肿与其抑制AQP4蛋白表达有关。     

Partial interruption of axonal transport due to microtubule breakage accounts for the formation of periodic varicosities after traumatic axonal injury

Due to their viscoelastic nature, white matter axons are susceptible to damage by high strain rates produced during traumatic brain injury (TBI). Indeed, diffuse axonal injury (DAI) is one of the most common features of TBI, characterized by the hallmark pathological profiles of axonal bulbs at disconnected terminal ends of axons and periodic swellings along axons, known as "varicosities." Although transport interruption underlies axonal bulb formation, it is unclear how varicosities arise, with multiple sites accumulating transported materials along one axon. Recently, axonal microtubules have been found to physically break during dynamic stretch injury of cortical axons in vitro. Here, the same in vitro model was used in parallel with histopathological analyses of human brains acquired acutely following TBI to examine the potential role of mechanical microtubule damage in varicosity formation post-trauma. Transmission electron microscopy (TEM) following in vitro stretch injury revealed periodic breaks of individual microtubules along axons that regionally corresponded with undulations in axon morphology. However, typically less than a third of microtubules were broken in any region of an axon. Within hours, these sites of microtubule breaks evolved into periodic swellings. This suggests axonal transport may be halted along one broken microtubule, yet can proceed through the same region via other intact microtubules. Similar axonal undulations and varicosities were observed following TBI in humans, suggesting primary microtubule failure may also be a feature of DAI. These data indicate a novel mechanism of mechanical microtubule damage leading to partial transport interruption and varicosity formation in traumatic axonal injury.     

Effects of progesterone on neurologic and morphologic outcome following diffuse traumatic brain injury in rats

Previous studies have identified that progesterone may be neuroprotective following traumatic brain injury (TBI). However, most of these have utilized models of TBI that produce a focal lesion or a significant ischemic component, neither of which is necessarily present in diffuse TBI. The current study uses a model of diffuse TBI in rats to examine the effects of progesterone on morphological changes and functional outcome following TBI. Male and ovariectomized female rats were subject to severe impact-acceleration injury under halothane anesthesia. After injury, animals were given a physiological, subcutaneous dose of progesterone (1.67 mg/kg) or equal volume of vehicle (sesame oil) daily throughout a 9-day neurologic assessment period where functional outcome was assessed using the rotarod and Barnes maze tests. There was a similar post-injury performance of male and ovariectomized female animals. Post-injury administration of progesterone improved the motor and cognitive performance of ovariectomized and male animals compared to vehicle-treated controls. Morphological differences between these animals, such as dark cell change, caspase-3 and APP immunoreactivity, were also investigated. Progesterone-treated males showed comparatively less dead or dying neurons, and marked attenuation of caspase-3 immunoreactivity. Both ovariectomized female and male animals treated with progesterone showed a profound reduction in axonal injury (seen via diminished APP immunoreactivity) when compared to controls. We conclude that physiological concentrations of progesterone administered after diffuse TBI confers beneficial effects on morphologic and functional outcome in both ovariectomized female and male animals.     

Attenuation of acute mitochondrial dysfunction after traumatic brain injury in mice by NIM811, a non-immunosuppressive cyclosporin A analog

Following traumatic brain injury (TBI), mitochondrial function becomes compromised. Mitochondrial dysfunction is characterized by intra-mitochondrial Ca(2+) accumulation, induction of oxidative damage, and mitochondrial permeability transition (mPT). Experimental studies show that cyclosporin A (CsA) inhibits mPT. However, CsA also inhibits calcineurin. In the present study, we conducted a dose-response analysis of NIM811, a non-calcineurin inhibitory CsA analog, on mitochondrial dysfunction following TBI in mice, and compared the effects of the optimal dose of NIM811 (10 mg/kg i.p.) against an optimized dose of CsA (20 mg/kg i.p.). Male CF-1 mice were subjected to severe TBI utilizing the controlled cortical impact model. Mitochondrial respiration was assessed from animals treated with either NIM811, CsA, or vehicle 15 min post-injury. The respiratory control ratio (RCR) of mitochondria from vehicle-treated animals was significantly (p<0.01) lower at 3 or 12 h post-TBI, relative to shams. Treatment of animals with either NIM811 or CsA significantly (p<0.03) attenuated this reduction. Consistent with this finding, both NIM811 and CsA significantly reduced lipid peroxidative and protein nitrative damage to mitochondria at 12 h post-TBI. These results showing the ability of NIM811 to fully duplicate the mitochondrial protective efficacy of CsA supports the conclusion that inhibition of the mPT may be sufficient to explain CsA's protective effects.     

Neuroprotective effect and cognitive outcome of chronic lithium on traumatic brain injury in mice

In vitro and in vivo studies have demonstrated that lithium treatment can protect neurons against excitotoxic and ischemic damage. Yet the possible beneficial effect of chronic low dose lithium on a model of traumatic brain injury (TBI) has not been intensively investigated. In this study, lithium (1 mmol/kg) was given daily, intraperitonealy, for 14 days before the onset of moderate controlled TBI and was continued until the mice were sacrificed. The results showed that in brain injured animals, chronic lithium treatment attenuated the loss of hemispheric tissue, cerebral edema and the expression of pro-inflammatory cytokine interleukin-1β. The neuronal degeneration in hippocampal CA3 and dentate gyrus sub-regions was also attenuated in the chronic lithium-treated mice as shown by Fluoro-Jade B staining. Moreover, chronic lithium treatment enhanced spatial learning and memory performance of injured mice in the Morris water maze. Our current study extended the protective role of lithium in the model of TBI and suggested that chronic lithium treatment might be a helpful therapeutic strategy for brain injury with multiple beneficial effects.     

Bumetanide administration attenuated traumatic brain injury through IL-1 overexpression

OBJECTIVE: To examine the effects of administration of bumetanide, a specific NKCC1 inhibitor, on traumatic brain injury (TBI)-induced interleukin-1 (IL-1) expression. METHODS: TBI model was induced by the calibrated weight drop device (450 g in weight, 2.0 m in height) in adult rats based on procedures previously reported. One hundred and sixty Wistar rats were divided into sham-control group and experimental group for time course works of TBI. The expression of IL-1beta brain edema and neuronal damage were determined in these animals after TBI. RESULTS: We found that both mRNA and protein of IL-1beta were up-regulated in the hippocampus 3-24 hours after TBI. Animals displayed severe brain edema and neuron damage after TBI. Bumetanide (15 mg/kg), a specific Na(+) -K(+) -2Cl(-) cotransporter inhibitor, significantly attenuated the TBI-induced neuronal damage by IL-1beta overexpression. The present study suggests that administration of bumetanide could significantly decreased TBI-induced inflammatory response and neuronal damage.     

The effects of combined fluid percussion traumatic brain injury and unilateral entorhinal deafferentation on the juvenile rat brain

The current study was designed to address the effects of traumatic brain injury (TBI) on plasticity and reorganization in the juvenile brain. Given that two of the major pathological sequelae of TBI involve a generalized neuroexcitation insult and diffuse axonal injury, we have employed models of these pathologies, delivered either independently or in combination, to examine their effects on injury-induced synaptic reorganization of the dentate gyrus in the developing rat. Postnatal day 28 rats received either sham, central fluid percussion traumatic brain injury (TBI), unilateral entorhinal cortical lesion (UEC), or TBI+UEC (TUEC) injury. Cognitive performance was assessed in the Morris water maze (MWM) between 11 and 15 days post-injury and the brains were processed for synaptophysin immunohistochemistry and routine electron microscopy. The MWM results revealed that TBI or UEC lesions delivered independently do not produce significant morbidity in P28 rats. However, when these injuries are combined, they reveal significant deficits in the MWM, accompanied by measurable changes in the distribution of presynaptic synaptophysin immunoreactivity over the deafferented dentate molecular layer. These observations are further supported by qualitative ultrastructural alterations in synaptic architecture in the same subregions of the dentate neuropil. The present findings show that the resilience of the immature brain following TBI is reduced when neuroexcitatory insult is combined with deafferentation. Moreover, when deafferented tissue is assessed morphologically, evidence exists for aberrant plasticity and abnormal synaptic reorganization in the juvenile brain.     

Continuous infusion of cyclosporin A postinjury significantly ameliorates cortical damage following traumatic brain injury

Traumatic brain injury (TBI) results in the rapid necrosis of cortical tissue at the site of injury. In the ensuing hours and days, secondary injury exacerbates the original damage resulting in significant neurological dysfunction. Recent reports from our lab demonstrate that a bolus injection of the immunosuppressant cyclosporin A (CsA) is neuroprotective following TBI. CsA transiently inhibits the opening of the mitochondrial permeability transition pore and maintains calcium homeostasis in isolated mitochondria. The present study utilized a unilateral controlled cortical impact model of TBI to assess whether the neuroprotective effects of CsA could be extended by chronic infusion. Adult rats were subjected to a moderate (2 mm) cortical deformation and the extent of cortical damage was assessed using modern stereological techniques. Animals were administrated a 20 mg/kg intraperitoneal bolus of CsA or vehicle 15 min postinjury and osmotic minipumps were implanted subcutaneously to deliver CsA (4.5 or 10 mg/kg/day) or vehicle. All animals receiving CsA demonstrated a significant reduction in lesion volume, with the highest dose offering the most neuroprotection (74% reduction in lesion volume). These results extend our previous findings and demonstrate that chronic infusion of CsA is neuroprotective following TBI. These findings also suggest that the mechanisms responsible for tissue necrosis following TBI are amenable to manipulation.     

A delayed and chronic treatment regimen with the 5-HT1A receptor agonist 8-OH-DPAT after cortical impact injury facilitates motor recovery and acquisition of spatial learning

An early (i.e., 15min) single systemic administration of the 5-HT(1A) receptor agonist 8-OH-DPAT enhances behavioral recovery after experimental traumatic brain injury (TBI). However, acute administration of pharmacotherapies after TBI may be clinically challenging and thus the present study sought to investigate the potential efficacy of a delayed and chronic 8-OH-DPAT treatment regimen. Forty-eight isoflurane-anesthetized adult male rats received either a controlled cortical impact or sham injury and beginning 24h later were administered 8-OH-DPAT (0.1 or 0.5mg/kg) or saline vehicle (1.0mL/kg) intraperitoneally once daily until all behavioral assessments were completed. Neurobehavior was assessed by motor and cognitive tests on post-operative days 1-5 and 14-19, respectively. The lower dose of 8-OH-DPAT (0.1mg/kg) enhanced motor performance, acquisition of spatial learning, and memory retention vs. both the higher dose (0.5mg/kg) and vehicle treatment (p<0.05). These data replicate previous findings from our laboratory showing that 8-OH-DPAT improves neurobehavior after TBI, and extend those results by demonstrating that the benefits can be achieved even when treatment is withheld for 24h. A delayed and chronic treatment regimen may be more clinically feasible.     

Dexamethasone suppresses infiltration of RhoA<Superscript>+</Superscript> cells into early lesions of rat traumatic brain injury

Inflammatory cell infiltration is a major part of secondary tissue damage in traumatic brain injury (TBI). RhoA is an important member of Rho GTPases and is involved in leukocyte migration. Inhibition of RhoA and its downstream target, Rho-associated coiled kinase (ROCK), has been proven to promote axon regeneration and function recovery following injury in the central nervous system (CNS). Previously, we showed that dexamethasone, an immunosuppressive corticosteroid, attenuated early expression of three molecules associated with microglia/macrophages activation following TBI in rats. Here, the effects of dexamethasone on the early expression of RhoA have been investigated in brains of TBI rats by immunohistochemistry. In brains of rats treated with TBI alone, significant RhoA⁺ cell accumulation was observed at 18 h post-injury and continuously increased during our observed time period. The accumulated RhoA⁺ cells were distributed to the areas of pannecrosis and selective neuronal loss. Most accumulated RhoA⁺ cells were identified as active microglia/macrophages by double-labelling. Dexamethasone (1 mg/kg body weight) was intraperitoneally injected on day 0 and 2 immediately following brain injury. Numbers of RhoA⁺ cells were significantly reduced on day 1 and 2 following administration of dexamethasone but returned to vehicle control level on day 4. However, dexamethasone treatment did not change the proportion of RhoA⁺ cells. These observations suggest that dexamethasone has only a transient effect on early leukocyte recruitment.     

The effects of cyclosporin-A on axonal conduction deficits following traumatic brain injury in adult rats

Immunophilin ligands, including cyclosporin-A (CsA), have been shown to be neuroprotective in experimental models of traumatic brain injury (TBI) and to attenuate the severity of traumatic axonal injury. Prior studies have documented CsA treatment to reduce essential components of posttraumatic axonal pathology, including impaired axoplasmic transport, spectrin proteolysis, and axonal swelling. However, the effects of CsA administration on axonal function, following TBI, have not been evaluated. The present study assessed the effects of CsA treatment on compound action potentials (CAPs) evoked in corpus callosum of adult rats following midline fluid percussion injury. Rats received a 20 mg/kg bolus of CsA, or cremaphor vehicle, at either 15 min or 1 h postinjury, and at 24 h postinjury CAP recording was conducted in coronal brain slices. To elucidate how injury and CsA treatments affect specific populations of axons, CAP waveforms generated largely by myelinated axons (N1) were analyzed separately from the CAP signal, which predominantly reflects activity in unmyelinated axons (N2). CsA administration at 15 min postinjury resulted in significant protection of CAP area, and this effect was more pronounced in N1, than in the N2, CAP component. This treatment also significantly protected against TBI-induced reductions in high-frequency responding of the N1 CAP signal. In contrast, CsA treatment at 1 h did not significantly protect CAPs but was associated with atypical waveforms in N1 CAPs, including decreased CAP duration and reduced refractoriness. The present findings also support growing evidence that myelinated and unmyelinated axons respond differentially to injury and neuroprotective compounds.     

Adult bone marrow stromal cells administered intravenously to rats after traumatic brain injury migrate into brain and improve neurological outcome

To measure effect of bone marrow stromal cells (MSCs) administered i.v. on rats subjected to traumatic brain injury (TBI), we injected MSCs labeled by BrdU into the tail vein 24 h after TBI and sacrificed rats 15 days later. The neurological severity score (NSS) and the Rotarod test were used to evaluate neurological function. The distribution of the donor cells in brain, heart, lung, kidney, liver and spleen were analyzed in recipient rats using immunohistochemical staining. MSCs injected i.v. significantly reduced motor and neurological deficits compared with control groups by day 15 after TBI. The cells preferentially entered and migrated into the parenchyma of the injured brain and expressed the neuronal marker NeuN and the astrocytic marker GFAP. MSCs were also found in other organs and primarily localized to the vascular structures, without any obvious adverse effects. Our data suggest that i.v. administration of MSCs may be useful in the treatment of 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.     

Posttraumatic administration of pituitary adenylate cyclase activating polypeptide in central fluid percussion injury in rats

Several in vitro and in vivo experiments have demonstrated the neuroprotective effects of pituitary adenylate cyclase activating polypeptide (PACAP) in focal cerebral ischemia, Parkinson's disease and traumatic brain injury (TBI). The aim of the present study was to analyze the effect of PACAP administration on diffuse axonal injury (DAI), an important contributor to morbidity and mortality associated with TBI, in a central fluid percussion (CFP) model of TBI. Rats were subjected to moderate (2 Atm) CFP injury. Thirty min after injury, 100 microg PACAP was administered intracerebroventricularly. DAI was assessed by immunohistochemical detection of beta-amyloid precursor protein, indicating impaired axoplasmic transport, and RMO-14 antibody, representing foci of cytoskeletal alterations (neurofilament compaction), both considered classical markers of axonal damage. Analysis of damaged, immunoreactive axonal profiles revealed significant axonal protection in the PACAP-treated versus vehicle-treated animals in the corticospinal tract, as far as traumatically induced disturbance of axoplasmic transport and cytoskeletal alteration were considered. Similarly to our former observations in an impact acceleration model of diffuse TBI, the present study demonstrated that PACAP also inhibits DAI in the CFP injury model. The finding indicates that PACAP and derivates can be considered potential candidates for further experimental studies, or purportedly for clinical trials in the therapy of TBI.     

Parálisis unilateral aislada del nervio oculomotor común posterior a trauma craneoencefálico leve

Isolated traumatic oculomotor nerve (ON) palsy is an uncommon clinical presentation of mild traumatic brain injury (TBI). There are very few cases in which it has been possible to demonstrate the isolated damage of the ON by avulsion of the roots, accompanied with traumatic axonal injury and intraneural microhemorrhage. We present a 23-year-old female who, after mild TBI, began to experience right ptosis, binocular diplopia, and photophobia. Clinical examination showed a complete ophthalmoparesis of the right ON, without other neurological deficits. Neuroimaging studies demonstrated no structural compressive damage of the right ON. Magnetic resonance imaging (MRI) with Gradient-echo and T1 weighted post-gadolinium was made, demonstrating signs of intraneural hemorrhage of the right ON, in addition to traumatic axonal injury extending from the right cerebral peduncle to the orbital fissure. Specific MRI protocols contribute as evidence of an isolated lesion to the ON.