IL-1 and its endogenous receptor antagonist (IL-1RaIL-1 appears to be involved in neuronal network excitability because it affects the turnover and release of various neurotransmitters (1) and the expression of neuropeptides and neurotrophic factors (3-5) and alters synaptic transmission and ionic currents (6-9) in several rodent forebrain regions.Convulsant stimuli increase the production of IL-1, its naturally occurring receptor antagonist (IL-1Ra), and IL-1R type I and II predominantly in glia in rodent central nervous system within hours of seizure induction (10-15).We recently showed that IL-1 prolongs hippocampal electroencephalographic (EEG) seizures in a N-methyl-D-aspartate receptor-dependent manner, and this action was blocked by .In this study, we investigated whether IL-1Ra has anticonvulsant properties in rodents. We found that intracerebral application of recombinant IL-1Ra or its endogenous overexpression in astrocytes potently inhibited behavioral and EEG seizures induced by bicuculline methiodide in mice. This effect was mediated specifically by IL-1R type I, because IL-1Ra was ineffective in knockout mice deficient in these receptors.Thus, the functional interaction between brain-born IL-1 and IL-1Ra during seizures, (i) may play a critical role in the physiopathological functions of IL-1, and (ii) may significantly affect the maintenance and spread of seizures. Materials and MethodsAnimals. Procedures involving animals and their care were conducted in conformity with institutional guidelines in compliance with national and international laws and policies (4D. L. N. 116, Gazzetta Ufficiale, supplement 40, 18-2-1992 and European
ABSTRACT:The cytokine interleukin-1 (IL-1) is produced by peripheral immune cells as well as glia and neurons within the brain; it plays a major role in immune to brain communication and in modulation of neural, neuroendocrine, and behavioral systems during illness. Although previous studies demonstrated that excess levels of IL-1 impaired memory processes and neural plasticity, it has been suggested that physiological levels of IL-1 are involved in hippocampal-dependent memory and long-term potentiation (LTP). To examine this hypothesis, we studied IL-1 receptor type I knockout (IL-1rKO) mice in several paradigms of memory function and hippocampal plasticity. In the spatial version of the water maze test, IL-1rKO mice displayed significantly longer latency to reach a hidden platform, compared with wild-type controls. Furthermore, IL-1rKO exhibited diminished contextual fear conditioning. In contrast, IL-1rKO mice were similar to control animals in hippocampal-independent memory tasks; i.e., their performance in the visually guided task of the water maze and the auditory-cued fear conditioning was normal. Electrophysiologically, anesthetized IL-1rKO mice exhibited enhanced paired-pulse inhibition in response to perforant path stimulation and no LTP in the dentate gyrus. In vitro, decreased paired-pulse responses, as well as a complete absence of LTP, were observed in the CA1 region of hippocampal slices taken from IL-1rKO mice compared with WT controls. These results suggest that IL-1 contributes to the regulation of memory processes as well as short-and long-term plasticity within the hippocampus. These findings have important implications to several conditions in humans, which are associated with long-term defects in IL-1 signaling, such as mutations in the IL-1 receptor accessory protein-like gene, which are involved in a frequent form of X-linked mental retardation.
Diabetes is a strong risk factor for premature and severe stroke. The GLP-1R (glucagon-like peptide-1 receptor) agonist Ex-4 (exendin-4) is a drug for the treatment of T2D (Type 2 diabetes) that may also have neuroprotective effects. The aim of the present study was to determine the efficacy of Ex-4 against stroke in diabetes by using a diabetic animal model, a drug administration paradigm and a dose that mimics a diabetic patient on Ex-4 therapy. Furthermore, we investigated inflammation and neurogenesis as potential cellular mechanisms underlying the Ex-4 efficacy. A total of seven 9-month-old Type 2 diabetic Goto–Kakizaki rats were treated peripherally for 4 weeks with Ex-4 at 0.1, 1 or 5 μg/kg of body weight before inducing stroke by transient middle cerebral artery occlusion and for 2–4 weeks thereafter. The severity of ischaemic damage was measured by evaluation of stroke volume and by stereological counting of neurons in the striatum and cortex. We also quantitatively evaluated stroke-induced inflammation, stem cell proliferation and neurogenesis. We show a profound anti-stroke efficacy of the clinical dose of Ex-4 in diabetic rats, an arrested microglia infiltration and an increase of stroke-induced neural stem cell proliferation and neuroblast formation, while stroke-induced neurogenesis was not affected by Ex-4. The results show a pronounced anti-stroke, neuroprotective and anti-inflammatory effect of peripheral and chronic Ex-4 treatment in middle-aged diabetic animals in a preclinical setting that has the potential to mimic the clinical treatment. Our results should provide strong impetus to further investigate GLP-1R agonists for their neuroprotective action in diabetes, and for their possible use as anti-stroke medication in non-diabetic conditions.
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