minocycline and Neurogenic-Inflammation

Developmental exposure to ethanol may cause fetal alcohol spectrum disorders (FASD), and the immature central nervous system (CNS) is particularly vulnerable to ethanol. In addition to vulnerability in the developing brain, we previously showed that ethanol also caused neuroapoptosis, microglial activation, and neuroinflammation in the spinal cord. Minocycline is an antibiotic that inhibits microglial activation and alleviates neuroinflammation. We sought to determine whether minocycline could protect spinal cord neurons against ethanol-induced damage. In this study, we showed that minocycline significantly inhibited ethanol-induced caspase-3 activation, microglial activation, and the expression of pro-inflammatory cytokines in the developing spinal cord. Moreover, minocycline blocked ethanol-induced activation of glycogen synthase kinase 3 beta (GSK3β), a key regulator of microglial activation. Meanwhile, minocycline significantly restored ethanol-induced inhibition of protein kinase B (AKT), mammalian target of the rapamycin (mTOR), and ERK1/2 signaling pathways, which were important pro-survival signaling pathways for neurons. Together, minocycline may attenuate ethanol-induced damage to the developing spinal cord by inhibiting microglial activation/neuroinflammation and by restoring the pro-survival signaling.

Topics: Animals; Anti-Bacterial Agents; Apoptosis; Caspase 3; Cytokines; Ethanol; Female; Glycogen Synthase Kinase 3 beta; Male; MAP Kinase Signaling System; Mice; Microglia; Minocycline; Neurogenic Inflammation; Proto-Oncogene Proteins c-akt; Spinal Cord; TOR Serine-Threonine Kinases

The neurological changes elicited by bacterial infection are called sickness behavior. Minocycline (MIN) is neuroprotective with a remarkable brain tissue penetration. MIN was orally administered at a dose 90 mg/kg for 3 days, whereas Escherichia coli was given as a single intraperitoneal injection (0.2 mL of 24 h growth) on the third day. After 24 h of bacterial infection, behavioral tests namely open field and forced swimming were carried out, then animals were decapitated. Rats infected with E. coli displayed reduced struggling time in forced swimming test, as well as, exploration and locomotion in open field test with reduction in neurotransmitters (norepinephrine, dopamine, and serotonin) versus elevation in the inflammatory (tumor necrosis factor-alpha, interferon-gamma) and oxidative stress (thiobarbituric acid reactive substance, reduced glutathione) biomarkers. Inflammatory infiltrates of nuclear cells were observed in brains of infected rats. MIN administration prevented the deleterious effects of E. coli infection, thus protects against sickness behavior possibly via defending from neuroinflammation.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Biomarkers; Brain; Brain Chemistry; Cytokines; Escherichia coli; Escherichia coli Infections; Glutathione; Illness Behavior; Male; Minocycline; Neurogenic Inflammation; Neurons; Neuroprotective Agents; Oxidation-Reduction; Oxidative Stress; Rats, Sprague-Dawley

Microglial activation in autonomic brain regions is a hallmark of neuroinflammation in neurogenic hypertension. Despite evidence that an impaired sympathetic nerve activity supplying the bone marrow (BM) increases inflammatory cells and decreases angiogenic cells, little is known about the reciprocal impact of BM-derived inflammatory cells on neuroinflammation in hypertension.. To test the hypothesis that proinflammatory BM cells from hypertensive animals contribute to neuroinflammation and hypertension via a brain-BM interaction.. After BM ablation in spontaneously hypertensive rats, and reconstitution with normotensive Wistar Kyoto rat BM, the resultant chimeric spontaneously hypertensive rats displayed significant reduction in mean arterial pressure associated with attenuation of both central and peripheral inflammation. In contrast, an elevated mean arterial pressure along with increased central and peripheral inflammation was observed in chimeric Wistar-Kyoto rats reconstituted with spontaneously hypertensive rat BM. Oral treatment with minocycline, an inhibitor of microglial activation, attenuated hypertension in both the spontaneously hypertensive rats and the chronic angiotensin II-infused rats. This was accompanied by decreased sympathetic drive and inflammation. Furthermore, in chronic angiotensin II-infused rats, minocycline prevented extravasation of BM-derived cells to the hypothalamic paraventricular nucleus, presumably via a mechanism of decreased C-C chemokine ligand 2 levels in the cerebrospinal fluid.. The BM contributes to hypertension by increasing peripheral inflammatory cells and their extravasation into the brain. Minocycline is an effective therapy to modify neurogenic components of hypertension. These observations support the hypothesis that BM-derived cells are involved in neuroinflammation, and targeting them may be an innovative strategy for neurogenic resistant hypertension therapy.

Topics: Angiotensin II; Animals; Baroreflex; Bone Marrow Cells; Bone Marrow Transplantation; Chemokine CCL2; Female; Hypertension; Interleukin-1beta; Male; Microglia; Minocycline; Neurogenic Inflammation; Norepinephrine; Paraventricular Hypothalamic Nucleus; Radiation Chimera; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sympathetic Nervous System; T-Lymphocyte Subsets

Compelling evidence has shown that diabetic metabolic disorder plays a critical role in the pathogenesis of Alzheimer's disease, including increased expression of β-amyloid protein (Aβ) and tau protein. Evidence has supported that minocycline, a tetracycline derivative, protects against neuroinflammation induced by neurodegenerative disorders or cerebral ischemia. This study has evaluated minocycline influence on expression of Aβ protein, tau phosphorylation, and inflammatory cytokines (interleukin-1β and tumor necrosis factor-α) in the brain of diabetic rats to clarify neuroprotection by minocycline under diabetic metabolic disorder.. An animal model of diabetes was established by high fat diet and intraperitoneal injection of streptozocin. In this study, we investigated the effect of minocycline on expression of Aβ protein, tau phosphorylation, and inflammatory cytokines (interleukin-1β and tumor necrosis factor-α) in the hippocampus of diabetic rats via immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay.. These results showed that minocycline decreased expression of Aβ protein and lowered the phosphorylation of tau protein, and retarded the proinflammatory cytokines, but not amyloid precursor protein.. On the basis of the finding that minocycline had no influence on amyloid precursor protein and beta-site amyloid precursor protein cleaving enzyme 1 which determines the speed of Aβ generation, the decreases in Aβ production and tau hyperphosphorylation by minocycline are through inhibiting neuroinflammation, which contributes to Aβ production and tau hyperphosphorylation. Minocycline may also lower the self-perpetuating cycle between neuroinflammation and the pathogenesis of tau and Aβ to act as a neuroprotector. Therefore, the ability of minocycline to modulate inflammatory reactions may be of great importance in the selection of neuroprotective agents, especially in chronic conditions like diabetes and Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Bacterial Agents; Diabetes Complications; Female; Hippocampus; Interleukin-1beta; Minocycline; Models, Animal; Neurogenic Inflammation; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; tau Proteins; Tumor Necrosis Factor-alpha

A growing body of evidence indicates that inflammation is one of the earliest neuropathological events in Alzheimer's disease. Accordingly, we have recently shown the occurrence of an early, pro-inflammatory reaction in the hippocampus of young, three-month-old transgenic McGill-Thy1-APP mice in the absence of amyloid plaques but associated with intracellular accumulation of amyloid beta petide oligomers. The role of such a pro-inflammatory process in the progression of the pathology remained to be elucidated.. To clarify this we administered minocycline, a tetracyclic derivative with anti-inflammatory and neuroprotective properties, to young, pre-plaque McGill-Thy1-APP mice for one month. The treatment ended at the age of three months, when the mice were still devoid of plaques. Minocycline treatment corrected the up-regulation of inducible nitric oxide synthase and cyclooxygenase-2 observed in young transgenic placebo mice. Furthermore, the down-regulation of inflammatory markers correlated with a reduction in amyloid precursor protein levels and amyloid precursor protein-related products. Beta-site amyloid precursor protein cleaving enzyme 1 activity and levels were found to be up-regulated in transgenic placebo mice, while minocycline treatment restored these levels to normality. The anti-inflammatory and beta-secretase 1 effects could be partly explained by the inhibition of the nuclear factor kappa B pathway.. Our study suggests that the pharmacological modulation of neuroinflammation might represent a promising approach for preventing or delaying the development of Alzheimer's disease neuropathology at its initial, pre-clinical stages. The results open new vistas to the interplay between inflammation and amyloid pathology.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Neuropathies; Amyloid Precursor Protein Secretases; Analysis of Variance; Animals; Animals, Newborn; Aspartic Acid Endopeptidases; Calcium-Binding Proteins; Cyclooxygenase 2; Disease Models, Animal; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Humans; Interleukin-1beta; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microfilament Proteins; Minocycline; Mutation; Neurogenic Inflammation; NFI Transcription Factors; Nitric Oxide Synthase Type II; Peptide Fragments

Neurogenic inflammation is induced by inflammatory mediators released in peripheral tissue from primary afferent nociceptors. Our previous studies suggest that neurogenic inflammation induced by intradermal injection of capsaicin results from the enhancement of dorsal root reflexes (DRRs), which involve antidromic activation of dorsal root ganglion (DRG) neurons. Numerous studies have reported the important role of glial modulation in pain. However, it remains unclear whether glial cells participate in the process of neurogenic inflammation-induced pain. Here we tested the role of DRG satellite glial cells (SGCs) in this process in anesthetized rats by administration of a glial inhibitor, minocycline. Electrical stimuli (ES, frequency 10 Hz; duration 1 ms; strength 3 mA) were applied to the cut distal ends of the L4-5 dorsal roots. The stimuli evoked antidromic action potentials designed to mimic DRRs. Local cutaneous blood flow in the hindpaw was measured using a Doppler flow meter. Antidromic ES for 10 min evoked a significant vasodilation that could be inhibited dose-dependently by local administration of the calcitonin gene-related peptide receptor antagonist, CGRP8-37. Pretreatment with capsaicin intradermally injected into the hindpaw 2h before the ES enhanced greatly the vasodilation evoked by antidromic ES, and this enhancement could be reversed by minocycline pretreatment. Our findings support the view that neurogenic inflammation following capsaicin injection involves antidromic activation of DRG neurons via the generation of DRRs. Inhibition of neurogenic inflammation by minocycline is suggested to be associated with its inhibitory effect on SGCs that are possibly activated following capsaicin injection.

Topics: Action Potentials; Animals; Capsaicin; Electric Stimulation; Ganglia, Spinal; Hindlimb; Injections, Intradermal; Male; Minocycline; Neurogenic Inflammation; Neuroglia; Nociceptors; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Satellite Cells, Perineuronal; Vasodilation