Biomedical subjects

Ishar Dalmau

Publications and source records attributed to Ishar Dalmau.

6 recordsLinked to original sources

PubMed2005

[Microglia--biology and relevance to disease].

Microglia, the resting macrophage population in the brain and spinal cord, has a central role in inflammatory processes and in acute and chronic degenerative diseases of the central nervous system. The possibility of utilizing microglia diagnostically has emerged with the prospect of visualization of reactive microgliosis via positron emission tomography. Microglia might also have a therapeutic potential by way of recruitment of microglial precursors from the blood with the opportunity to introduce genetically modified cells lesion-specifically into the central nervous system via the bloodstream. Knowledge about microglial function has preferentially been obtained via studies in experimental animal models of the pathological central nervous system. In spite of the rather extensive knowledge regarding the pathophysiological implications of these cells, their function in the normal central nervous system remains rather unknown.

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PubMed2005

Proliferating resident microglia express the stem cell antigen CD34 in response to acute neural injury.

Reactive microgliosis is a highly characteristic response to neural injury and disease, which may influence neurodegenerative processes and neural plasticity. We have investigated the origin and characteristics of reactive microglia in the acute phase of their activation in the dentate gyrus following transection of the entorhino-dentate perforant path projection. To investigate the possible link between microglia and hematopoietic precursors, we analyzed the expression of the stem cell marker CD34 by lesion-reactive microglia in conjunction with the proliferation marker bromodeoxyuridine (BrdU) and the use of radiation bone marrow (BM) chimeric mice. We found that CD34 is upregulated on early-activated resident microglia, rather than by infiltrating bone marrow-derived cells. The number of CD34(+) microglia peaked at day 3 when 67% of the resident CD11b/Mac-1(+) microglia co-expressed CD34, and all CD34(+) cells co-expressed Mac-1, and decreased sharply toward day 5, unlike Mac-1, which was maximally expressed at day 5. Approximately 80% of the CD34(+) cells in the denervated dentate gyrus had incorporated BrdU into their nuclei at day 3. We also showed that CD34 is upregulated on early-activated microglia in the facial motor nucleus following peripheral axotomy. The results suggest lesion-reactive microglia to consist of functionally distinct subpopulations of cells; a major population of activated resident CD34(+)Mac-1(+) microglia with a high capacity for self-renewal, and a subpopulation of CD34(-)Mac-1(+) microglia which has a mixed extrinsic and intrinsic origin and whose proliferative capacity is unknown.

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PubMed2005

Microglial cell population dynamics in the injured adult central nervous system.

Reactive microgliosis is characteristic of trauma and stroke as well as inflammatory and chronic neurodegenerative disease. A conspicuous feature of the microglial reaction to acute neural injury is a massive expansion of the microglial cell population which peaks a few days following injury. New data based on the use of radiation bone marrow-chimeric mice suggest this expansion also involves recruitment of bone marrow-derived cells, which migrate into the neural parenchyma and differentiate into microglia. Here, we discuss the contribution of bone marrow-derived cells to the injury-induced expansion of the microglial cell population, seen in the dentate gyrus with ongoing anterograde axonal and terminal synaptic degeneration, subsequent to transection of the entorhino-dentate perforant path projection. In this paradigm of minor brain injury, the bone marrow-derived cells are grossly outnumbered by activated resident microglia, which express the stem cell antigen CD34 concurrent to a marked capacity for self-renewal. The observation of a mixed origin of lesion-reactive microglia, consisting of a smaller subpopulation of exogenous bone marrow-derived microglia, and a larger population of activated resident microglia, the majority of which express CD34 and undergo proliferation, suggests that lesion-reactive microglia consist of functionally distinct cell populations. The demonstration of an injury-enhanced recruitment of bone marrow-derived cells into the perforant path-denervated dentate gyrus, raises the possibility of using genetically manipulated cells as vectors for lesion-site-specific gene therapy even in minimally injured areas of the central nervous system.

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PubMed2003

Dynamics of microglia in the developing rat brain.

Entrance of mesodermal precursors into the developing CNS is the most well-accepted origin of microglia. However, the contribution of proliferation and death of recruited microglial precursors to the final microglial cell population remains to be elucidated. To investigate microglial proliferation and apoptosis during development, we combined proliferating cell nuclear antigen (PCNA) immunohistochemistry, in situ detection of nuclear DNA fragmentation (TUNEL), and caspase-3 immunohistochemistry with tomato lectin histochemistry, a selective microglial marker. The study was carried out in Wistar rats from embryonic day (E) 16 to postnatal day (P) 18 in cerebral cortex, subcortical white matter, and hippocampus. Proliferating microglial cells were found at all ages in the three brain regions and represented a significant fraction of the total microglial cell population. The percentage of microglia expressing PCNA progressively increased from the embryonic period (25-51% at E16) to a maximum at P9, when the great majority of microglia expressed PCNA (92-99%) in all the brain regions analyzed. In spite of the remarkable proliferation and expansion of the microglial population with time, the density of microglia remained quite constant in most brain regions because of the considerable growth of the brain during late prenatal and early postnatal periods. In contrast, apoptosis of microglia was detected only at certain times and was restricted to some ameboid cells in white matter and primitive ramified cells in gray matter, representing a small fraction of the microglial population. Therefore, our results point to proliferation of microglial precursors in the developing brain as a physiological mechanism contributing to the acquisition of the adult microglial cell population. In contrast, microglial apoptosis occurs only locally at certain developmental stages and thus seems less crucial for the establishment of the final density of microglia.

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PubMed2003

Aggravated brain damage after hypoxic ischemia in immature adenosine A2A knockout mice.

BACKGROUND AND PURPOSE: Cerebral hypoxic ischemia (HI) is an important cause of brain injury in the newborn infant. Adenosine is believed to protect against HI brain damage. However, the roles of the different adenosine receptors are unclear, particularly in young animals. We examined the role of adenosine A2A receptors (A2AR) using 7-day-old A2A knockout (A2AR(-/-)) mice in a model of HI. METHODS: HI was induced in 7-day-old CD1 mice by exposure to 8% oxygen for 30 minutes after occlusion of the left common carotid artery. The resulting unilateral focal lesion was evaluated with the use of histopathological scoring and measurements of residual brain areas at 5 days, 3 weeks, and 3 months after HI. Behavioral evaluation of brain injury by locomotor activity, rotarod, and beam-walking test was made 3 weeks and 3 months after HI. Cortical cerebral blood flow, assessed by laser-Doppler flowmetry, and rectal temperature were measured during HI. RESULTS: Reduction in cortical cerebral blood flow during HI and rectal temperature did not differ between wild-type (A2AR(+/+)) and knockout mice. In the A2AR(-/-) animals, brain injury was aggravated compared with wild-type mice. The A2AR(-/-) mice subjected to HI displayed increased forward locomotion and impaired rotarod performance in adulthood compared with A2AR(+/+) mice subjected to HI, whereas beam-walking performance was similarly defective in both groups. CONCLUSIONS: These results suggest that, in contrast to the situation in adult animals, A2AR play an important protective role in neonatal HI brain injury.

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PubMed2003

Estimation of absolute microglial cell numbers in mouse fascia dentata using unbiased and efficient stereological cell counting principles.

Stereology offers a set of unbiased principles to obtain precise estimates of total cell numbers in a defined region. In terms of microglia, which in the traumatized and diseased CNS is an extremely dynamic cell population, the strength of stereology is that the resultant estimate is unaffected by shrinkage or expansion of the tissue. The optical fractionator technique is very efficient but requires relatively thick sections (e.g., > or =20 microm after coverslipping) and the unequivocal identification of labeled cells throughout the section thickness. We have adapted our protocol for Mac-1 immunohistochemical visualization of microglial cells in thick (70 microm) vibratome sections for stereological counting within the murine hippocampus, and we have compared the staining results with other selective microglial markers: the histochemical demonstration of nucleotide diphosphatase (NDPase) activity and the tomato lectin histochemistry. The protocol gives sections of high quality with a final mean section thickness of >20 microm (h=22.3 microm +/- 0.64 microm), and with excellent rendition of Mac-1+ microglia through the entire height of the section. The NDPase staining gives an excellent visualization of microglia, although with this thickness, the intensity of the staining is too high to distinguish single cells. Lectin histochemistry does not visualize microglia throughout the section and, accordingly, is not suited for the optical fractionator. The mean total number of Mac-1+ microglial cells in the unilateral dentate gyrus of the normal young adult male C57BL/6 mouse was estimated to be 12,300 (coefficient of variation (CV)=0.13) with a mean coefficient of error (CE) of 0.06. The perspective of estimating microglial cell numbers using stereology is to establish a solid basis for studying the dynamics of the microglial cell population in the developing and in the injured, diseased and normal adult CNS.

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