Regulation of Kir4.1 expression in astrocytes and astrocytic tumors: a role for interleukin-1 beta

<p>Abstract</p> <p>Objective</p> <p>Decreased expression of inwardly rectifying potassium (Kir) channels in astrocytes and glioma cells may contribute to impaired K⁺ buffering and increased propensity for seizures. Here, we evaluated the potential effect of inflammatory molecules, such as interleukin-1β (IL-1β) on Kir4.1 mRNA and protein expression.</p> <p>Methods</p> <p>We investigated Kir4.1 (Kcnj10) and IL-1β mRNA expression in the temporal cortex in a rat model of temporal lobe epilepsy 24 h and 1 week after induction of status epilepticus (SE), using real-time PCR and western blot analysis. The U373 glioblastoma cell line and human fetal astrocytes were used to study the regulation of Kir4.1 expression in response to pro-inflammatory cytokines. Expression of Kir4.1 protein was also evaluated by means of immunohistochemistry in surgical specimens of patients with astrocytic tumors (<it>n</it> = 64), comparing the expression in tumor patients with (<it>n</it> = 38) and without epilepsy (<it>n</it> = 26).</p> <p>Results</p> <p>Twenty-four hours after onset of SE, Kir4.1 mRNA and protein were significantly down-regulated in temporal cortex of epileptic rats. This decrease in expression was followed by a return to control level at 1 week after SE. The transient downregulation of Kir4.1 corresponded to the time of prominent upregulation of IL-1β mRNA. Expression of Kir4.1 mRNA and protein in glial cells in culture was downregulated after exposure to IL-1β. Evaluation of Kir4.1 in tumor specimens showed a significantly lower Kir4.1 expression in the specimens of patients with epilepsy compared to patients without epilepsy. This paralleled the increased presence of activated microglial cells, as well as the increased expression of IL-1β and the cytoplasmic translocation of high mobility group box 1 (HMGB1).</p> <p>Conclusions</p> <p>Taken together, these findings indicate that alterations in expression of Kir4.1 occurring in epilepsy-associated lesions are possibly influenced by the local inflammatory environment and in particular by the inflammatory cytokine IL-1β.</p

The waking brain: an update

Wakefulness and consciousness depend on perturbation of the cortical soliloquy. Ascending activation of the cerebral cortex is characteristic for both waking and paradoxical (REM) sleep. These evolutionary conserved activating systems build a network in the brainstem, midbrain, and diencephalon that contains the neurotransmitters and neuromodulators glutamate, histamine, acetylcholine, the catecholamines, serotonin, and some neuropeptides orchestrating the different behavioral states. Inhibition of these waking systems by GABAergic neurons allows sleep. Over the past decades, a prominent role became evident for the histaminergic and the orexinergic neurons as a hypothalamic waking center

NSAIDs in animal models of Alzheimer’s Disease

Brain inflammation is an underlying factor in the pathogenesis of Alzheimer’s disease (AD) and epidemiological studies indicate that sustained use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of AD and may delay its onset or slow its progression. Nevertheless, recent clinical trials have shown that NSAIDs do not alter the progression of AD. Neuroinflammation occurs in vulnerable regions of the AD brain where highly insoluble β-amyloid (Aβ) peptide deposits and neurofibrillary tangles, as well as damaged neurons and neurites, provide stimuli for inflammation. To elucidate the complex role of inflammation in neurodegenerative processes and the efficacy of NSAIDs in AD we developed an animal model of neuroinflammation/neurodegeneration in vivo. An “artificial plaque” was formed by injecting aggregated ß-amyloid peptide (A(1-40) or A(1-42)) into the nucleus basalis magnocellularis (NBM) of rats. We investigated several aspects of the neuroinflammatory reaction around the “artificial plaque” such as microglia and astrocyte activation, production of proinflammatory compounds, activation of cyclooxigenase-2 (COX-2), p38 Mitogen Activated Protein Kinase (p38MAPK) and induction of inducible Nitric Oxide Synthase (iNOS). Finally, degeneration of cortically projecting cholinergic neurons was also evaluated by means of immunohistochemistry and microdialysis. We examined whether the attenuation of brain inflammatory reaction by NSAIDs and NO-donors may protect neurons against neurodegeneration. The data reported in this review show that in in vivo model of brain inflammation and neurodegeneration, the administration of NSAIDs and NO-donors prevent not only the inflammatory reaction, but also the cholinergic hypofunction. Our data may help elucidating the role of neuroinflammation in the pathogenesis of AD and the ability of anti-inflammatory agents to reduce the risk of developing AD and to slow its progression