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Michael Nilsson

Publications and source records attributed to Michael Nilsson.

17 recordsLinked to original sources
PubMed2006

Less neurogenesis and inflammation in the immature than in the juvenile brain after cerebral hypoxia-ischemia.

The effects of hypoxia-ischemia (HI) on proliferation and differentiation in the immature (postnatal day 9) and juvenile (postnatal day 21) mouse hippocampus were investigated by injecting bromodeoxyuridine (50 mg/kg) daily for 7 days after the insult and evaluating the labeling 5 weeks after HI. Phenotypic differentiation was evaluated using NeuN, Iba1, APC, and S100beta as markers of neurons, microglia, oligodendrocytes, and astrocytes, respectively. The basal proliferation, in particular neurogenesis, was higher in the immature than in the juvenile hippocampus. Hypoxia-ischemia did not increase neurogenesis significantly in the immature dentate gyrus (DG), but it increased several-fold in the juvenile brain, reaching the same level as in the normal, noninjured immature brain. This suggests that the immature hippocampus is already working at the top of its proliferative capacity and that even though basal neurogenesis decreased with age, the injury-induced generation of new neurons in the juvenile hippocampus could not increase beyond the basal level of the immature brain. Generation of glial cells of all three types after HI was significantly more pronounced in the cornu ammonis of the hippocampus region of the juvenile hippocampus. In the DG, only microglia production was greater in the juvenile brain. Increased microglia proliferation correlated with increased levels of the proinflammatory cytokines MCP-1 and IL-18 3 days after HI, indicating that the inflammatory response is stronger in the juvenile hippocampus. In summary, contrary to what has been generally assumed, our results indicate that the juvenile brain has a greater capacity for neurogenesis after injury than the immature brain.

Aging↗
PubMed2006

The metabolism of C-glucose by neurons and astrocytes in brain subregions following focal cerebral ischemia in rats.

To provide insights into the effects of temporary focal ischemia on the function of neurons and astrocytes in vivo, we measured the incorporation of radiolabel from [U-14C]glucose into both glutamate and glutamine in brain subregions at 1 h of reperfusion following occlusion of the middle cerebral artery for 2 or 3 h. Under the experimental conditions used, 14C-glutamate is mainly produced in neurons whereas 14C-glutamine is generated in astrocytes from 14C-glutamate of both neuronal and astrocytic origin. Radiolabel incorporation into both amino acids was greatly decreased. The change in 14C-glutamate accumulation provides strong evidence for substantial reductions in neuronal glucose metabolism. The resulting decrease in delivery of 14C-glutamate from the neurons to astrocytes was probably also the major contributor to the change in 14C-glutamine content. These alterations probably result in part from a marked depression of glycolytic activity in the neurons, as suggested by previous studies assessing deoxyglucose utilization. Alterations in 14C-glucose metabolism were not restricted to tissue that would subsequently become infarcted. Thus, these changes did not inevitably lead to death of the affected cells. The ATP : ADP ratio and phosphocreatine content were essentially preserved during recirculation following 2 h of ischemia and showed at most only moderate losses in some subregions following 3 h of ischemia. This retention of energy reserves despite the decreases in 14C-glucose metabolism in neurons suggests that energy needs were substantially reduced in the post-ischemic brain. Marked increases in tissue lactate accumulation during recirculation, particularly following 3 h of ischemia, provided evidence that impaired pyruvate oxidation probably also contributed to the altered 14C-glucose metabolism. These findings indicate the presence of complex changes in energy metabolism that are likely to greatly influence the responses of neurons and astrocytes to temporary focal ischemia.

Adenosine Diphosphate↗
PubMed2005

Astrocyte activation and reactive gliosis.

Astrocytes become activated (reactive) in response to many CNS pathologies, such as stroke, trauma, growth of a tumor, or neurodegenerative disease. The process of astrocyte activation remains rather enigmatic and results in so-called "reactive gliosis," a reaction with specific structural and functional characteristics. In stroke or in CNS trauma, the lesion itself, the ischemic environment, disrupted blood-brain barrier, the inflammatory response, as well as in metabolic, excitotoxic, and in some cases oxidative crises--all affect the extent and quality of reactive gliosis. The fact that astrocytes function as a syncytium of interconnected cells both in health and in disease, rather than as individual cells, adds yet another dimension to this picture. This review focuses on several aspects of astrocyte activation and reactive gliosis and discusses its possible roles in the CNS trauma and ischemia. Particular emphasis is placed on the lessons learnt from mouse genetic models in which the absence of intermediate filament proteins in astrocytes leads to attenuation of reactive gliosis with distinct pathophysiological and clinical consequences.

Animals↗
PubMed2005

Astrocytic function assessed from 1-14C-acetate metabolism after temporary focal cerebral ischemia in rats.

Astrocytes play many roles essential for normal brain activity. The ability of these cells to recover after temporary focal cerebral ischemia is likely to be one important determinant of the extent of brain dysfunction and tissue damage. We have assessed astrocytic function based on the incorporation of radiolabel from 1-14C-acetate into glutamine at 1 hour of recirculation after middle cerebral artery occlusion for 2 or 3 hours in rats. There were marked differences in the response between subregions within the tissue subjected to ischemia, but the overall pattern of changes was similar after each ischemic period. The striatum, which forms part of the severely ischemic focal tissue during arterial occlusion, showed a large (44% to 68%) decrease in glutamine labeling compared with equivalent tissue from the contralateral hemisphere. In contrast, 14C-glutamine content was not significantly altered in perifocal tissue in the cerebral cortex, which was subjected to more moderate ischemia. Cortical focal tissue also was not significantly affected, but the response was much more variable between rats. In these brain subregions, the extent of recovery of the 14C-acetate metabolism after ischemia was not a good predictor of the likelihood of subsequent infarct development. Interestingly, a similar pattern of responses persisted when recirculation was extended to 4 hours. These results indicate that many astrocytes, particularly in the cortex, remain viable and capable of at least some complex oxidative metabolism during the first few hours of recirculation.

Acetates↗
PubMed2005

Gap junction blockage limits intercellular spreading of astrocytic apoptosis induced by metabolic depression.

Astrocytes are highly coupled by gap junction channels, which allow transfer of intracellular signalling molecules and metabolites between connected cells. Astrocytic gap junctions remain open during ischemic conditions as previously demonstrated in vitro and in situ. In this study, we investigated the effect of gap junction blockage on iodoacetate-induced ATP depression and cell death progression in astrocytes in primary rat hippocampal cultures. We demonstrated that blockage of gap junctions during iodoacetate-induced inhibition of the glycolysis induced an earlier onset of the ATP depression. Moreover, initiation of apoptotic processes, demonstrated by binding of Annexin V, was critically dependent on the ATP levels. The apoptotic event was also shown to spread and involve neighbouring cells, a process that was inhibited by blockage of gap junction communication. Chelating intracellular calcium using BAPTA-AM decelerated the iodoacetate-induced ATP depression. The chelation also decelerated the spreading of apoptotic processes. Inhibition of caspases did not alter the expansion of cell groups being Annexin V positive. However, the proportion of Annexin V positive cells also being propidium iodide positive was increased after caspase inhibition. The results show that inhibition of gap junctions during cellular metabolic depression interferes with the metabolic status and cell death progression in astrocytes.

Adenosine Triphosphate↗
PubMed2005

Development of a test environment to evaluate performance of modern hearing aid features.

This article describes a new test environment and materials with the potential to measure performance differences among different hearing aid signal processing methods and features. Normative data suggest a linearly predictable increase in difficulty on a speech-in-noise task as the masker changes from random noise to multiple-talker speech, and the number of talkers increases. Data collected with normal listeners revealed no differences across four test sites for the single loudspeaker (Noise-Front) results and some differences across test sites for the multiple loudspeaker results. Room dimension differences among audiometric test enclosures and diffusion (or lack thereof) of the maskers in the vertical and horizontal dimensions of the sound fields appear to account for performance differences for the multiloudspeaker arrays, confirming the need to limit maskers to aperiodic signals in rooms with controlled ceiling height or to establish norms for each test environment such that results obtained in different enclosures can be compared.

Adult↗
PubMed2004

Highly selective and prolonged depletion of mitochondrial glutathione in astrocytes markedly increases sensitivity to peroxynitrite.

Glutathione, a major endogenous antioxidant, is found in two intracellular pools in the cytoplasm and the mitochondria. To investigate the importance of the smaller mitochondrial pool, we developed conditions based on treatment with ethacrynic acid that produced near-complete and highly selective depletion of mitochondrial glutathione in cultured astrocytes. Recovery of mitochondrial glutathione was only partial over several hours, suggesting slow net uptake from the cytoplasm. Glutathione depletion alone did not significantly affect mitochondrial membrane potential, ATP content, or cell viability when assessed after 24 hr, although the activities of respiratory chain complexes were altered. However, these astrocytes showed a greatly enhanced sensitivity to 3-morpholinosydnonimine, a peroxynitrite generator. Treatment with 200 microm 3-morpholinosydnonimine produced decreases within 3 hr in mitochondrial membrane potential and ATP content and caused the release of lactate dehydrogenase, contrasting with preservation of these properties in control cells. These properties deteriorated further by 24 hr in the glutathione-depleted cells and were associated with morphological changes indicative of necrotic cell death. This treatment enhanced the alterations in activities of the respiratory chain complexes observed with glutathione depletion alone. Cell viability was markedly improved by cyclosporin A, suggesting a role for the mitochondrial permeability transition in the astrocytic death. These studies provide the most direct evidence available for any cell type on the roles of mitochondrial glutathione. They demonstrate the critical importance of this metabolite pool in protecting against peroxynitrite-induced damage in astrocytes and indicate a key contribution in determining the activities of respiratory chain components.

Adenosine Triphosphate↗
PubMed2004

Glutathione monoethyl ester provides neuroprotection in a rat model of stroke.

Oxidative stress plays an important role in the development of tissue damage following transient focal cerebral ischaemia. Glutathione is a central component in the antioxidant defence of cells. We have previously shown a close association between mitochondrial glutathione loss and cell death following middle cerebral artery (MCA) occlusion. Glutathione monoethyl ester increases cellular glutathione and is particularly effective in increasing the mitochondrial pool. In the present investigation, we infused glutathione monoethyl ester into the third ventricle during 2 h of MCA occlusion and 48 h of reperfusion. Infarct size was reduced from 46% of the total ischaemic hemisphere in saline-treated animals to 16% following ester treatment. Thus, glutathione monoethyl ester provides neuroprotection following transient focal cerebral ischaemia.

Animals↗
PubMed2004

Reloading the retina by modifying the glial matrix.

Remarkably, removing the major structural elements from astrocytes and Müller glia in the mouse retina makes successful integration and differentiation of stem cells into the retina more likely, as revealed by Kinouchi et al. These ground-breaking results throw up several new conundrums in understanding the process of stem cell recruitment, differentiation and incorporation into the retina, but they also suggest novel ways to treat retinal degenerative diseases.

Animals↗
PubMed2004

Glutathione monoethylester prevents mitochondrial glutathione depletion during focal cerebral ischemia.

Glutathione is a central component in the antioxidant defences of cells. We have recently reported an early and selective loss of total (reduced plus oxidised) glutathione from mitochondria isolated from rat brain following occlusion of the middle cerebral artery. This mitochondrial glutathione depletion showed an apparent association with the tissue damage that developed during subsequent reperfusion, suggesting that it could be an important determinant of susceptibility to cell loss. In the present study, we have investigated whether in vivo treatment with glutathione ethyl ester can modulate mitochondrial glutathione in the brain and whether this treatment can influence the response to focal ischemia. In further support of our previous findings, middle cerebral artery occlusion caused a duration-dependent partial loss of mitochondrial glutathione. Bilateral injections of glutathione ethyl ester immediately prior to induction of unilateral focal ischemia resulted in a substantial increase in glutathione in mitochondria from the striatum of both the non-ischemic hemisphere (190% of saline-treated controls) and the ischemic hemisphere (240% of controls) at 2h after arterial occlusion. Total tissue glutathione was not affected by the ester treatment at this time. A smaller increase in mitochondrial glutathione was observed at 3h of occlusion in the non-ischemic striatum following ester treatment but at this time point glutathione was not significantly altered in mitochondria from the ischemic hemisphere. Pre-ischemic treatment with glutathione ester did not significantly change the volume of tissue infarction assessed at 48 h following ischemia for 2 or 3h. These studies demonstrate that glutathione ethyl ester is a highly effective modulator of the mitochondrial glutathione pool in the intact brain and provides a useful means for further investigating the role of this antioxidant in the development of tissue damage in ischemia and other brain disorders.

Animals↗
PubMed2004

Increased mitochondrial permeability in response to intrastriatal N-methyl-D-aspartate: detection based on accumulation of radiolabel from [3H]deoxyglucose.

Induction of the mitochondrial permeability transition has been proposed as an important contributor to cell loss in several neurological disorders, but the evidence that this change can develop in cells in the intact mature brain is largely indirect. In this study, we have tested whether an intrastriatal injection of N-methyl-D-aspartate results in increases in inner membrane permeability that can be detected from mitochondrial accumulation of metabolites of 3H-deoxyglucose previously taken up by brain cells. An increase in incorporation of deoxyglucose metabolites was found in mitochondria prepared from the striatum but not from cerebral cortex distant from the injection site. This change developed more than 8 h after treatment with N-methyl-D-aspartate and is consistent with the induction of the permeability transition as a late change in the progression to irreversible neuronal damage in response to this excitotoxic insult. At earlier times, the restricted permeability of the inner mitochondrial membrane was apparently preserved, at least sufficiently to prevent significant diffusion of metabolites between the cytoplasm and the matrix.

Animals↗
PubMed2003

Losses of NG2 and NeuN immunoreactivity but not astrocytic markers during early reperfusion following severe focal cerebral ischemia.

The ability of glia to recover essential functions following a period of focal cerebral ischemia is likely to be one important factor influencing the severity of tissue damage that subsequently develops. In this study, we have compared changes in immunoreactivity of markers specific for astrocytes, NG2-positive glia and neurons in tissue subregions during early reperfusion following 3 h of middle cerebral artery occlusion to provide insights into possible differential susceptibility of these cell populations. Under the conditions used, infarction ultimately encompasses most of the perfusion territory of the occluded artery. Nonetheless, alterations in immunoreactivity during the first 3 h of recirculation were restricted to brain regions that had been subjected to severe ischemia. In the striatum, cellular immunoreactivity for NG2 and neuronal markers, NeuN and microtubule-associated protein 2, was greatly reduced by 1 h of reperfusion and declined further at 3 h. NG2 labeling of blood vessels in the striatum appeared post-ischemically, mimicking expression of this protein during development. Less severe changes were seen in the neuronal markers in overlying cerebral cortex. In contrast to the losses of other cellular proteins, immunoreactivity for the astrocytic marker, glial fibrillary acidic protein, was preserved in all tissue that had been subjected to severe ischemia and labeling of another astrocytic protein, glutamine synthetase, was increased by 3 h of reperfusion. These findings provide the first evidence of marked sensitivity of NG2-immunoreactivity to severe ischemia and suggest a greater initial resistance of astrocytes compared with neurons and NG2-positive glia to ischemia-reperfusion damage.

Animals↗
PubMed2003

Fluorocitrate-mediated astroglial dysfunction causes seizures.

A role for astroglia in epileptogenesis has been hypothesised but is not established. Low doses of fluorocitrate specifically and reversibly disrupt astroglial metabolism by blocking aconitase, an enzyme integral to the tricarboxylic acid cycle. We used cerebral cortex injections of fluorocitrate, at a dose that we demonstrated to inhibit astroglial metabolism selectively, to determine whether astroglial disturbances lead to seizures. Rats were halothane-anesthetized, and 0.8 nmol of sodium fluorocitrate was injected into the cerebral cortex. Extradural electroencephalogram (EEG) electrodes were implanted, after which the anesthesia was ceased and the animals were observed. In all experiments, 14 of 15 fluorocitrate-treated animals exhibited epileptiform EEG discharges, with some animals exhibiting convulsive seizures. Discharges commenced as early as 30 min postfluorocitrate injection. Intraperitoneal octanol, but not halothane by inhalation, given to test the possible participation of gap junctions in EEG discharge generation, blocked or delayed the occurrence of discharges after fluorocitrate. These results indicate that focal cerebrocortical astroglial dysfunction leads to focal epileptiform discharges and sometimes to convulsive seizures and that the process possibly depends on effects mediated by gap junctions.

Animals↗
PubMed2003

[Neurobiology provides a scientific foundation for rehabilitation. Report from an international symposium].

The increasing knowledge regarding central nervous function and plasticity is of great importance for modern rehabilitation. In a recent symposium, the themes covered were brain plasticity, motor control, spasticity and pain modulation. It was demonstrated that the cortex is dynamic with respect to structure as well as function, which can be observed both spontaneously and after rehabilitation interventions. An enriched environment has been proven to be of great importance for regeneration and plasticity in the central nervous system. This is also clear regarding activation and survival of the neural stem cells. "Constraint-induced therapy" has aroused considerable interest but controlled studies are needed for evaluation. The increasing knowledge regarding motor control and spasticity gives a valuable platform for clinical interventions. Knowledge about modulation of pain signals within the central nervous system will increase the therapeutic possibilities at long-standing pain, for example, concerning increased sensitivity and impaired inhibition.

Brain Diseases↗
PubMed2003

Astrocytes and stroke: networking for survival?

Astrocytes are now known to be involved in the most integrated functions of the central nervous system. These functions are not only necessary for the normally working brain but are also critically involved in many pathological conditions, including stroke. Astrocytes may contribute to damage by propagating spreading depression or by sending proapoptotic signals to otherwise healthy tissue via gap junction channels. Astrocytes may also inhibit regeneration by participating in formation of the glial scar. On the other hand, astrocytes are important in neuronal antioxidant defense and secrete growth factors, which probably provide neuroprotection in the acute phase, as well as promoting neurogenesis and regeneration in the chronic phase after injury. A detailed understanding of the astrocytic response, as well as the timing and location of the changes, is necessary to develop effective treatment strategies for stroke patients.

Astrocytes↗
PubMed2002

Insulin-like growth factor-I and neurogenesis in the adult mammalian brain.

In most brain regions of highly developed mammals, the majority of neurogenesis is terminated soon after birth. However, new neurons are continually generated throughout life in the subventricular zone and the dentate gyrus of the hippocampus. Insulin-like growth factor-I (IGF-I) is a polypeptide hormone that has demonstrated effects on these progenitor cells. IGF-I induces proliferation of isolated progenitors in culture, as well as affecting various aspects of neuronal induction and maturation. Moreover, systemic infusion of IGF-I increases both proliferation and neurogenesis in the adult rat hippocampus, and uptake of serum IGF-I by the brain parenchyma mediates the increase in neurogenesis induced by exercise. Neurogenesis in the adult brain is regulated by many factors including aging, chronic stress, depression and brain injury. Aging is associated with reductions in both hippocampal neurogenesis and IGF-I levels, and administration of IGF-I to old rats increases neurogenesis and reverses cognitive impairments. Similarly, stress and depression also inhibit neurogenesis, possibly via the associated reductions in serotonin or increases in circulating glucocorticoids. As both of these changes have the potential to down regulate IGF-I production by neural cells, stress may inhibit neurogenesis indirectly via downregulation of IGF-I. In contrast, brain injury stimulates neurogenesis, and is associated with upregulation of IGF-I in the brain. Thus, there is a tight correlation between IGF-I and neurogenesis in the adult brain under different conditions. Further studies are needed to clarify whether IGF-I does indeed mediate neurogenesis in these situations.

Aging↗