Ipsilateral Thalamus Research Articles

Pontocerebellar Angle Aspergillosis

Cerebral aspergillosis is a rare and severe condition mostly affecting immunocompromised patients. The lesions are usually intra-axial and supratentorial; several radiologic patterns have been reported. A 65-year-old patient with chronic lymphocytic leukemia presented with fever, headache, and a pontocerebellar syndrome. A brain magnetic resonance imaging (MRI) showed a ring-enhancing left pontocerebellar mass consistent with an infectious disease. Despite broad-spectrum antibiotic therapy, the patient worsened. A follow-up MRI examination disclosed a concomitant acute ischemic lesion in the ipsilateral thalamus and an irregular narrowing of the posterior cerebral artery close to the lesion. A retrospective analysis of the first MRI revealed a small mesencephalic ischemic lesion, contiguous to the extra-axial pontocerebellar mass. At surgical inspection the mass was found to be an extra-axial granuloma, with purulent components, attached to the petrous-tentorial angle, surrounded by a thick capsule. The lesion was only partially removed because of the tight relationship with the leptomeninges of the brain stem. Cerebral aspergillosis was the final histologic and microbiological diagnosis. In immunocompromised patients, the coexistence of an infectious lesion with involvement of contiguous vessels and consequent ischemic infarction should raise the suspicion of aspergillosis, even in unusual locations such as the pontocerebellar angle.

Unilateral thalamic hypometabolism on FDG brain PET in patient with temporal lobe epilepsy

Interictal Brain F-18 fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) imaging has been widely used for localizing the focus of a seizure. Hypometabolism in the extratemporal cortex on FDG-PET study is an important finding to localize seizure focus, which might be seen as ipsilateral, contralateral or bilateral thalamus hypometabolism in epileptic patients. In this case report, it is aimed to show ipsilateral thalamus hypomethabolism on FDG PET brain study of a 24-year-old male patient with temporal lobe epilepsy.

Inhibition of Na+/H+ Exchanger Isoform 1 Is Neuroprotective in Neonatal Hypoxic Ischemic Brain Injury

We investigated the role of Na(+)/H(+) exchanger isoform 1 (NHE-1) in neonatal hypoxia/ischemia (HI). HI was induced by unilateral ligation of the left common carotid artery in postnatal day 9 (P9) mice, and subsequent exposure of animals to 8% O(2) for 55 min. A pre/posttreatment group received a selective and potent NHE-1 inhibitor HOE 642 (0.5 mg/kg, intraperitoneally) 5 min before HI, then at 24 and 48 h after HI. A posttreatment group received HOE 642 (0.5 mg/kg) at 10 min, 24 h, and 48 h after HI. Saline injections were used as vehicle controls. The vehicle-control brains at 72 h after HI exhibited neuronal degeneration in the ipsilateral hippocampus, striatum, and thalamus, as identified with Fluoro-Jade C positive staining and loss of microtubule-associated protein 2 (MAP2) expression. NHE-1 protein was upregulated in glial fibrillary acidic protein-positive reactive astrocytes. In HOE 642-treated brains, the morphologic hippocampal structures were better preserved and displayed less neurodegeneration and a higher level of MAP2 expression. Motor-learning deficit was detected at 4 weeks of age after HI in the vehicle control group. Inhibition of NHE-1 in P9 mice not only reduced neurodegeneration during the acute stage of HI but also improved the striatum-dependent motor learning and spatial learning at 8 weeks of age after HI. These findings suggest that NHE-1-mediated disruption of ionic homeostasis contributes to striatal and CA1 pyramidal neuronal injury after neonatal HI.

Chronic Hyperperfusion and Angiogenesis Follow Subacute Hypoperfusion in the Thalamus of Rats with Focal Cerebral Ischemia

Cerebral blood flow (CBF) is disrupted after focal ischemia in rats. We examined long-term hemodynamic and cerebrovascular changes in the rat thalamus after focal cerebral ischemia. Cerebral blood flow quantified by arterial spin labeling magnetic resonance imaging was decreased in the ipsilateral and contralateral thalamus 2 days after cerebral ischemia. Partial thalamic CBF recovery occurred by day 7, then the ipsilateral thalamus was chronically hyperperfused at 30 days and 3 months compared with its contralateral side. This contrasted with permanent hypoperfusion in the ipsilateral cortex. Angiogenesis was indicated by endothelial cell (RECA-1) immunohistochemistry that showed increased blood vessel branching in the ipsilateral thalamus at the end of the 3-month follow-up. Only transient thalamic IgG extravasation was observed, indicating that the blood-brain barrier was intact after day 2. Angiogenesis was preceded by transiently altered expression levels of cadherin family adhesion molecules, cadherin-7, protocadherin-1, and protocadherin-17. In conclusion, thalamic pathology after focal cerebral ischemia involved long-term hemodynamic changes and angiogenesis preceded by altered expression of vascular adhesion factors. Postischemic angiogenesis in the thalamus represents a novel type of remote plasticity, which may support removal of necrotic brain tissue and aid functional recovery.

Association of Chronic Vascular Changes with Functional Outcome after Traumatic Brain Injury in Rats

We tested the hypothesis that vascular remodeling in the cortex, hippocampus, and thalamus is associated with long-term functional recovery after traumatic brain injury (TBI). We induced TBI with lateral fluid-percussion (LFP) injury in adult rats. Animals were followed-up for 9 months, during which we tested motor performance using a neuroscore test, spatial learning and memory with a Morris water maze, and seizure susceptibility with a pentylenetetrazol (PTZ) test. At 8 months, they underwent structural MRI, and cerebral blood flow (CBF) was assessed by arterial spin labeling (ASL) MRI. Then, rats were perfused for histology to assess the density of blood vessels. In the perilesional cortex, the CBF decreased by 56% (p < 0.01 compared to controls), and vessel density increased by 28% (p < 0.01). There was a negative correlation between CBF in the perilesional cortex and vessel density (r = -0.75, p < 0.01). However, in the hippocampus, we found a 13% decrease in CBF ipsilaterally (p < 0.05) and 20% contralaterally (p < 0.01), and no change in vessel number. In the ipsilateral thalamus, the increase in CBF (34%, p < 0.01) was associated with a remarkable increase in vessel density (78%, p < 0.01). Animals showed motor impairment that was not associated with vascular changes. Instead, poor performance in the Morris water maze correlated with enhanced thalamic vessel density (r = -0.81, p < 0.01). Finally, enhanced seizure susceptibility was associated with reduced CBF in the ipsilateral hippocampus (r = 0.78, p < 0.05) and increased vascular density in the thalamus (r = 0.69, p < 0.05). There was little interaction between the behavioral measures. The present study demonstrates that each of the investigated brain areas has a unique pattern of vascular abnormalities. Chronic alterations in CBF could not be attributed to changes in vascular density. Association of thalamic hypervascularity to epileptogenesis warrants further studies. Finally, hippocampal hypoperfusion may predict later seizure susceptibility in the LFP injury model of TBI, which could be of value for pre-clinical antiepileptogenesis trials.

Synergism of human amnion-derived multipotent progenitor (AMP) cells and a collagen scaffold in promoting brain wound recovery: Pre-clinical studies in an experimental model of penetrating ballistic-like brain injury

One of the histopathological consequences of a penetrating ballistic brain injury is the formation of a permanent cavity. In a previous study using the penetrating ballistic-like brain injury (PBBI) model, engrafted human amnion-derived multipotent progenitor (AMP) cells failed to survive when injected directly in the injury tract, suggesting that the cell survival requires a supportive matrix. In this study, we seated AMP cells in a collagen-based scaffold, injected into the injury core, and investigated cell survival and neuroprotection following PBBI. AMP cells suspended in AMP cell conditioned medium (ACCS) or in a liquefied collagen matrix were injected immediately after a PBBI along the penetrating injury tract. Injured control rats received only liquefied collagen matrix. All animals were allowed to survive two weeks. Consistent with our previous results, AMP cells suspended in ACCS failed to survive; likewise, no collagen was identified at the injury site when injected alone. In contrast, both AMP cells and the collagen were preserved in the injury cavity when injected together. In addition, AMP cells/collagen treatment preserved some apparent brain tissue in the injury cavity, and there was measurable infiltration of endogenous neural progenitor cells and astrocytes into the preserved brain tissue. AMP cells were also found to have migrated into the subventricular zone and the corpus callosum. Moreover, the AMP cell/collagen treatment significantly attenuated the PBBI-induced axonal degeneration in the corpus callosum and ipsilateral thalamus and improved motor impairment on rotarod performance. Overall, collagen-based scaffold provided a supportive matrix for AMP cell survival, migration, and neuroprotection.

Deletion of the p53 tumor suppressor gene improves neuromotor function but does not attenuate regional neuronal cell loss following experimental brain trauma in mice

Deletion of the tumor suppressor gene p53 has been shown to improve the outcome in experimental models of focal cerebral ischemia and kainate-induced seizures. To evaluate the potential role of p53 in traumatic brain injury, genetically modified mice lacking a functional p53 gene (p53(-/-), n = 9) and their wild-type littermates (p53(+/+), n = 9) were anesthetized and subjected to controlled cortical impact (CCI) experimental brain trauma. After brain injury, neuromotor function was assessed by using composite neuroscore and rotarod tests. By 7 days posttrauma, p53(-/-) mice exhibited significantly improved neuromotor function, in the composite neuroscore (P = 0.002) as well as in two of three individual tests, when compared with brain-injured p53(+/+) animals. CCI resulted in the formation of a cortical cavity (mean volume = 6.1 mm(3)) 7 days postinjury in p53(+/+) as well as p53(-/-) mice. No difference in lesion volume was detected between the two genotypes (P = 0.95). Although significant cell loss was detected in the ipsilateral hippocampus and thalamus of brain-injured animals, no differences between p53(+/+) and p53(-/-) mice were detected. Although our results suggest that lack of the p53 gene results in augmented recovery of neuromotor function following experimental brain trauma, they do not support a role for p53 acting as a mediator of neuronal death in this context, underscoring the complexity of its role in the injured brain.

Detection and quantification of remote microglial activation in rodent models of focal ischaemia using the TSPO radioligand CLINDE

Neuroinflammation is involved in stroke pathophysiology and might be imaged using radioligands targeting the 18 kDa translocator protein (TSPO). We studied microglial reaction in brain areas remote from the primary lesion site in two rodent models of focal cerebral ischaemia (permanent or transient) using [125I]-CLINDE, a promising TSPO single photon emission computed tomography radioligand. In a mouse model of permanent middle cerebral artery occlusion (MCAO), ex vivo autoradiographic studies demonstrated, besides in the ischaemic territory, accumulation of [125I]-CLINDE in the ipsilateral thalamus with a binding that progressed up to 3 weeks after MCAO. [125I]-CLINDE binding markedly decreased in animals pre-injected with either unlabelled CLINDE or PK11195, while no change was observed with flumazenil pre-treatment, demonstrating TSPO specificity. In rats subjected to transient MCAO, [125I]-CLINDE binding in the ipsilateral thalamus and substantia nigra pars reticulata (SNr) was significantly higher than that in contralateral tissue. Moreover, [125I]-CLINDE binding in the thalamus and SNr was quantitatively correlated to the ischaemic volume assessed by MRI in the cortex and striatum, respectively. Clinical consequences of secondary neuronal degeneration in stroke might be better treated thanks to the discrimination of neuronal processes using in vivo molecular imaging and potent TSPO radioligands like CLINDE to guide therapeutic interventions.

How common is brain atrophy in patients with medial temporal lobe epilepsy?

It is unclear whether extrahippocampal brain damage in patients with medial temporal lobe epilepsy (MTLE) is a homogeneous phenomenon, as most data relates to the average volume reduction in groups of patients. This study aimed to evaluate where and how much atrophy is to be expected in an individual patient with MTLE. High-resolution T(1) magnetic resonance imaging (MRI) was obtained from 23 consecutive patients with unilateral MTLE and from a matched control group. Parametric tests of voxel-based gray matter volume evaluated mean regional atrophy in MTLE compared with controls. Gray matter images were then submitted to a voxel by voxel calculation of the fitted receiver operating characteristic (ROC) curve area, plotting the sensitivity versus 1-specificity for a binary classifier (MTLE vs. controls). The area under the curve (AUC) was calculated for each voxel and a resulting three-dimensional map of gray matter voxel-wise AUCs was obtained. On average, patients with MTLE showed atrophy in the ipsilateral hippocampus and on a limbic network. Elevated AUC was demonstrated in the ipsilateral hippocampus and medial temporal lobe, the ipsilateral thalamus and occipitotemporal cortex, the ipsilateral cerebellum, the cingulate, the contralateral insula, and the occipitoparietal and dorsolateral prefrontal cortex. This study suggests that the medial temporal lobe, occipitotemporal areas, the cerebellum, the cingulate cortex, the ipsilateral insula, and thalamus are more likely to be atrophied in randomly selected patients with MTLE. Structures such as the orbitofrontal cortex, the contralateral medial temporal areas and insula, the putamen, and the caudate may be atrophied, but not as consistently.

Reduction of β-Amyloid Deposits by γ-Secretase Inhibitor is Associated with the Attenuation of Secondary Damage in the Ipsilateral Thalamus and Sensory Functional Improvement after Focal Cortical Infarction in Hypertensive Rats

Abnormal β-amyloid (Aβ) deposits in the thalamus have been reported after cerebral cortical infarction. In this study, we investigated the association of Aβ deposits, with the secondary thalamic damage after focal cortical infarction in rats. Thirty-six stroke-prone renovascular hypertensive rats were subjected to distal middle cerebral artery occlusion (MCAO) and then randomly divided into MCAO, vehicle, and N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) groups and 12 sham-operated rats as control. The DAPT was administered orally at 72 hours after MCAO. Seven days after MCAO, sensory function, neuron loss, and glial activation and proliferation were evaluated using adhesive removal test, Nissl staining, and immunostaining, respectively. Thalamic Aβ accumulation was evaluated using immunostaining and enzyme-linked immunosorbent assay (ELISA). Compared with vehicle group, the ipsilateral thalamic Aβ, neuronal loss, glial activation and proliferation, and the mean time to remove the stimulus from right forepaw significantly decreased in DAPT group. The mean time to remove the stimulus from the right forepaw and thalamic Aβ burden were both negatively correlated with the number of thalamic neurons. These findings suggest that Aβ deposits are associated with the secondary thalamic damage. Reduction of thalamic Aβ by γ-secretase inhibitor may attenuate the secondary damage and improve sensory function after cerebral cortical infarction.

Involvement of the thalamocortical network in TLE with and without mesiotemporal sclerosis

The thalamus plays an important role in seizure propagation in temporal lobe epilepsy (TLE). This study investigated how structural abnormalities in the focus, ipsilateral thalamus and extrafocal cortical structures relate to each other in TLE with mesiotemporal sclerosis (TLE-MTS) and without hippocampal sclerosis (TLE-no). T₁ and high-resolution T₂ images were acquired on a 4T magnet in 29 controls, 15 TLE-MTS cases, and 14 TLE-no. Thalamus volumes were obtained by warping a labeled atlas onto each subject's brain. Deformation-based morphometry was used to identify regions of thalamic volume loss and FreeSurfer for cortical thickness measurements. CA1 volumes were obtained from high-resolution T₂ images. Multiple regression analysis and correlation analyses for voxel- and vertex-based analyses were performed in SPM2 and FreeSurfer. TLE-MTS had bilateral volume loss in the anterior thalamus, which was correlated with CA1 volume and cortical thinning in the mesiotemporal lobe. TLE-no had less severe volume loss in the dorsal lateral nucleus, which was correlated with thinning in the mesiotemporal region but not with extratemporal thinning. The findings suggest that seizure propagation from the presumed epileptogenic focus or regions close to it into the thalamus occurs in TLE-MTS and TLE-no and results in circumscribed neuronal loss in the thalamus. However, seizure spread beyond the thalamus seems not to be responsible for the extensive extratemporal cortical abnormalities in TLE.

Long‐term changes in the ipsilateral substantia nigra after transient focal cerebral ischaemia in rats

Transient focal cerebral ischaemia can cause neuronal damage in remote areas, including the ipsilateral thalamus and subsutantia nigra, as well as in the ischaemic core. In the present study, we investigated long-term changes in the ipsilateral substantia nigra from 1 up to 20 weeks after 90 min of transient focal cerebral ischaemia in rats, using tyrosine hydroxylase (TH), neuronal nuclei (NeuN), Iba-1, glial fibrillary acidic protein (GFAP) and brain-derived neurotrophic factor (BDNF) immunostaining. These results show that transient focal cerebral ischaemia in rats can cause a severe and prolonged neuronal damage in the ipsilateral striatum. Our results with TH and NeuN immunostaining also demonstrate that the atrophy of the ipsilateral substantia nigra after transient focal cerebral ischaemia was not static but progressive. Furthermore, our double-labelled immunohistochemical study suggests that BDNF released by GFAP-positive astrocytes may play a key role in the survival of dopaminergic neurones in the ipsilateral substantia nigra at the chronic stage after transient focal cerebral ischaemia, although the areas of the ipsilateral substantia nigra are decreased progressively after ischaemia. Thus our study provides further valuable information for the pathogenesis of neuronal damage after transient focal cerebral ischaemia.

Magnetic Resonance Imaging of Regional Hemodynamic and Cerebrovascular Recovery after Lateral Fluid-Percussion Brain Injury in Rats

Hemodynamic and cerebrovascular factors are crucially involved in secondary damage after traumatic brain injury (TBI). With magnetic resonance imaging, this study aimed to quantify regional cerebral blood flow (CBF) by arterial spin labeling and cerebral blood volume by using an intravascular contrast agent, during 14 days after lateral fluid-percussion injury (LFPI) in rats. Immunohistochemical analysis of vessel density was used to evaluate the contribution of vascular damage. Results show widespread ipsilateral and contralateral hypoperfusion, including both the cortex and the hippocampus bilaterally, as well as the ipsilateral thalamus. Hemodynamic unrest may partly be explained by an increase in blood vessel density over a period of 2 weeks in the ipsilateral hippocampus and perilesional cortex. Furthermore, three phases of perilesional alterations in CBF, progressing from hypoperfusion to normal and back to hypoperfusion within 2 weeks were shown for the first time in a rat TBI model. These three phases were similar to hemodynamic fluctuations reported in TBI patients. This makes it feasible to use LFPI in rats to study mechanisms behind hemodynamic changes and to explore novel therapeutic approaches for secondary brain damage after TBI.

Adenosine A1 Receptor Activation as a Brake on the Microglial Response after Experimental Traumatic Brain Injury in Mice

We reported that adenosine A(1) receptor (A(1)AR) knockout (KO) mice develop lethal status epilepticus after experimental traumatic brain injury (TBI), which is not seen in wild-type (WT) mice. Studies in epilepsy, multiple sclerosis, and neuro-oncology suggest enhanced neuro-inflammation and/or neuronal death in A(1)AR KO. We hypothesized that A(1)AR deficiency exacerbates the microglial response and neuronal damage after TBI. A(1)AR KO and WT littermates were subjected to mild controlled cortical impact (3 m/sec; 0.5 mm depth) to left parietal cortex, an injury level below the acute seizure threshold in the KO. At 24 h or 7 days, mice were sacrificed and serial sections prepared. Iba-1 immunostaining was used to quantify microglia at 7 days. To assess neuronal injury, sections were stained with Fluoro-Jade C (FJC) at 24 h to evaluate neuronal death in the hippocampus and cresyl violet staining at 7 days to analyze cortical lesion volumes. We also studied the effects of adenosine receptor agonists and antagonists on (3)H-thymidine uptake (proliferation index) by BV-2 cells (immortalized mouse microglial). There was no neuronal death in CA1 or CA3 quantified by FJC. A(1)AR KO mice exhibited enhanced microglial response; specifically, Iba-1 + microglia were increased 20-50% more in A(1)AR KO versus WT in ipsilateral cortex, CA3, and thalamus, and contralateral cortex, CA1, and thalamus (p < 0.05). However, contusion and cortical volumes did not differ between KO and WT. Pharmacological studies in cultured BV-2 cells indicated that A(1)AR activation inhibits microglial proliferation. A(1)AR activation is an endogenous inhibitor of the microglial response to TBI, likely via inhibition of proliferation, and this may represent a therapeutic avenue to modulate microglia after TBI.

An optimized voxel‐based morphometric study of gray matter changes in patients with left‐sided and right‐sided mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE/HS)

To determine whether changes in gray matter volume (GMV) differ according to the affected side in mesial temporal lobe epilepsy/hippocampal sclerosis (MTLE/HS) syndrome, and moreover to test the hypothesis of more pronounced structural changes in right-sided MTLE/HS. This hypothesis (especially that the contralateral thalamus is more affected in right-sided MTLE/HS) arose from the results of our recent study, wherein more expressed structural and functional changes were observed in a small sample of patients with right-sided MTLE/HS (Brázdil et al., 2009). Twenty patients with left-sided and 20 with right-sided MTLE/HS and 40 sex- and age-matched healthy controls were included in the study. Voxel-based morphometry (VBM) with a modulation step was applied to magnetic resonance imaging (MRI) brain images. Statistical parametric maps were used to compare structural changes between patients and controls separately for the left- and right-sided MTLE/HS subgroups. We also compared the local GMV of the brain structures (insula and thalamus) between the subgroups of patients. In the subgroup with right-sided MTLE/HS, a reduction of GMV was detected in the mesiotemporal structures and the ipsilateral thalamus (as in left-sided MTLE/HS), but also notably in the ipsilateral insula and contralateral thalamus. A statistical analysis revealed a significantly more extensive reduction of GMV in the ipsilateral/contralateral insula and the contralateral thalamus in the subgroup with right-sided compared to left-sided MTLE/HS. We found asymmetrical morphologic changes in patients with left- and right-sided MTLE/HS syndrome (more pronounced in right-sided MTLE/HS). These differences could be theoretically explained by different neuronal networks and pathophysiologic changes in temporolimbic structures.

Hippocampal malrotation in pediatric patients with epilepsy associated with complex prefrontal dysfunction

The cognitive consequences of hippocampal malrotation (HIMAL) were investigated in a matched control study of children with epilepsy. Seven children with HIMAL were compared on a range of memory and attention tasks with 21 control children with epilepsy without temporal role pathology and 7 children with epilepsy and magnetic resonance imaging (MRI)-documented hippocampal sclerosis. In addition, in a statistical morphometric analysis, MRI studies from four children with HIMAL were compared to similar images of 20 age-matched typically developing control children. Although the task battery was sensitive to the memory deficit of the children with hippocampal sclerosis, it did not reveal memory impairment in the patients with HIMAL. In contrast, the patients with HIMAL were impaired on the attentionally more demanding dual tasks, compared to both the control and the hippocampal sclerosis group. The structural MRI analysis revealed morphometric abnormalities in the tail of the affected hippocampus, the adjacent neocortex, and the ipsilateral medial thalamus. The basal forebrain was bilaterally affected. Abnormalities in remote cortex were found in the ipsilateral temporal lobe, the contralateral anterior cingulate gyrus, and bilateral in the dorsolateral and lateral-orbitofrontal prefrontal cortex. Because the prefrontal cortical regions have been shown to be active during dual-task performance, the MRI results converge with the neuropsychological findings of impairment on these tasks. We conclude that HIMAL had no direct memory repercussions, but was secondary to subtle but widespread neurologic abnormalities that also affected morphology and functioning of the prefrontal cortex.

Artificial Dental Pulp Exposure Injury Up-regulates Antigen-Presenting Cell–related Molecules in Rat Central Nervous System

Introduction Bacterial infection and resulting inflammation of the dental pulp might not only trigger neuroimmune interactions in this tissue but also sensitize the central nervous system (CNS) such as the thalamus via nociceptive neurons. Thus, immunopathologic changes in the rat thalamus that take place after pulp inflammation were investigated. Methods Pulp exposure was made in mandibular right first molars of 5-week-old Wistar rats. After 24 hours, the thalamus was retrieved and subjected to either immunohistochemistry for class II major histocompatibility complex (MHC) molecules and glial fibrillary acidic protein (GFAP) or mRNA expression analysis of antigen-presenting cell–related molecules and N-methyl- D-aspartate receptor 2D subunit (NR2D) by means of reverse transcription–polymerase chain reaction (RT-PCR) and real-time PCR. Results At 24 hours after pulp exposure, the density of class II MHC molecule–expressing and GFAP-expressing cells was increased in the contralateral thalamus. Gene expression analysis revealed the up-regulation of class II MHC molecules, CD80, CD83, CD86, and NR2D in the contralateral thalamus, as compared with the ipsilateral thalamus. Conclusions These results suggest the signal of pulp inflammation induces neuronal activation in the CNS.

Role of CCL2 (MCP-1) in Traumatic Brain Injury (TBI): Evidence from Severe TBI Patients and CCL2−/− Mice

Cerebral inflammation involves molecular cascades contributing to progressive damage after traumatic brain injury (TBI). The chemokine CC ligand-2 (CCL2) (formerly monocyte chemoattractant protein-1, MCP-1) is implicated in macrophage recruitment into damaged parenchyma after TBI. This study analyzed the presence of CCL2 in human TBI, and further investigated the role of CCL2 in physiological and cellular mechanisms of secondary brain damage after TBI. Sustained elevation of CCL2 was detected in the cerebrospinal fluid (CSF) of severe TBI patients for 10 days after trauma, and in cortical homogenates of C57Bl/6 mice, peaking at 4 to 12 h after closed head injury (CHI). Neurological outcome, lesion volume, macrophage/microglia infiltration, astrogliosis, and the cerebral cytokine network were thus examined in CCL2-deficient (-/-) mice subjected to CHI. We found that CCL2-/- mice showed altered production of multiple cytokines acutely (2 to 24 h); however, this did not affect lesion size or cell death within the first week after CHI. In contrast, by 2 and 4 weeks, a delayed reduction in lesion volume, macrophage accumulation, and astrogliosis were observed in the injured cortex and ipsilateral thalamus of CCL2-/- mice, corresponding to improved functional recovery as compared with wild-type mice after CHI. Our findings confirm the significant role of CCL2 in mediating post-traumatic secondary brain damage.

Physiology of epilepsia partialis continua and subcortical mechanisms of status epilepticus

Physiology of epilepsia partialis continua and subcortical mechanisms of status epilepticus

Human Amnion-Derived Multipotent Progenitor Cell Treatment Alleviates Traumatic Brain Injury-Induced Axonal Degeneration

To identify a viable cell source with potential neuroprotective effects, we studied amnion-derived multipotent progenitor (AMP) cells in a rat model of penetrating ballistic-like brain injury (PBBI). AMP cells were labeled with fluorescent dye PKH26 and injected in rats immediately following right hemispheric PBBI or sham PBBI surgery by ipsilateral i.c.v. administration. At 2 weeks post-injury, severe necrosis developed along the PBBI tract and axonal degeneration was prominent along the corpus callosum (cc) and in the ipsilateral thalamus. Injected AMP cells first entered the subventricular zone (SVZ) in both sham and PBBI rats. Further AMP cell migration along the cc only occurred in PBBI animals. No significant difference in injury volume was observed across all treatment groups. In contrast, treatment with AMP cells significantly attenuated axonal degeneration in both the thalamus and the cc. Interestingly, PKH26-labeled AMP cells were detected only in the SVZ and the cc (in parallel with the axonal degeneration), but not in the thalamus. None of the labeled AMP cells appeared to express neural differentiation, as evidenced by the lack of double labeling with nestin, S-100, GFAP, and MAP-2 immunostaining. In conclusion, AMP cell migration was specifically induced by PBBI and requires SVZ homing, yet the neuroprotective effect of intracerebral ventrical treatment using AMP cells was not limited to the area where the cells were present. This suggests that the attenuation of the secondary brain injury following PBBI was likely to be mediated by mechanisms other than cell replacement, possibly through delivery or sustained secretion of neurotrophic factors.