Minocycline Prevents Osmotic Demyelination Syndrome by Inhibiting the Activation of Microglia

Abstract

Rapid correction of chronic hyponatremia can lead to osmotic demyelination syndrome (ODS), a severe demyelination disease. The microglia that accumulate in the demyelinative lesions may play a detrimental role in the pathogenesis of ODS by producing proinflammatory cytokines, suggesting that they may be a target for therapeutic intervention. Here, we investigated whether minocycline, a selective and potent inhibitor of microglial activation, could protect against ODS in rats. We induced hyponatremia by liquid diet feeding and dDAVP infusion. Rapid correction of the hyponatremia 7 days later resulted in neurologic impairment with severe demyelinative lesions. Activated microglia accumulated at the site of demyelination. Treatment with minocycline within 24 hours of rapid correction, however, was protective: rats exhibited minimal neurologic impairment, and survival improved. Histologic analysis showed that minocycline inhibited demyelination and suppressed the accumulation of microglia at the site of demyelination. Real-time RT-PCR and immunohistochemical analyses showed that minocycline inhibited the activity of microglia and the expression of inflammatory cytokines (e.g. IL-1␤, inducible nitric-oxide synthase, and TNF-␣), monocyte chemoattractant protein-1, and matrix metalloproteinase-12 in microglia. These results demonstrate that minocycline can protect against ODS by inhibiting the activation and accumulation of microglia at the site of demyelinative lesions, suggesting its possible use in clinical practice.

GABA Type B Receptor Signaling in Proopiomelanocortin Neurons Protects Against Obesity, Insulin Resistance, and Hypothalamic Inflammation in Male Mice on a High-Fat Diet

“…These results suggest that the deletion of GABA B Rs in POMC neurons leads to hypothalamic inflammation on a HFD. There is evidence to suggest that hypothalamic inflammation is related to the onset of obesity (Gregor and Hotamisligil, 2011), and previous studies showed that hypothalamic inflammation occurred even in WT mice on a HFD (Zhang et al, 2008;Kirchner et al, 2012;Thaler et al, 2012). Together with the findings in the present study, it is suggested that GABA B Rs in POMC neurons are essential to protect the hypothalamus from inflammation on a HFD.…”

“…Together with the findings in the present study, it is suggested that GABA B Rs in POMC neurons are essential to protect the hypothalamus from inflammation on a HFD. It is also reported that, with a HFD, gliosis in the hypothalamus is increased and that POMC neurons died by autophagy (Thaler et al, 2012). In contrast, our data showed there is no increase in the expression of gliosis markers (Gfap or CD68) or neuronal loss of POMC.…”

“…8). Expression levels of Gfap and CD68, makers of astrocyte and microglia activation, respectively (Thaler et al, 2012), were not significantly different between groups (Fig. 8).…”

“…Immunohistochemistry was performed in mice at the age of 16 weeks as described previously (Suzuki et al, 2010). The antibodies of GAD67 and vGLUT2 were purchased from Millipore, and those of Synapsin 1, EGFP, and POMC precursor from Synaptic System, MBL, and Phoenix Pharmaceuticals, respectively.…”

Chronic Hyponatremia Causes Neurologic and Psychologic Impairments

“…Rats had ad libitum access to standard chow and tap water until the induction of hyponatremia according to previously described methods. [51][52][53] Briefly, osmotic minipumps (Alzet model 2002 or 2004; DURECT Corporation, Cupertino, CA) containing dDAVP (10 mg/ml; Kyowa Hakko Kogyo Co. Ltd., Tokyo, Japan) were implanted subcutaneously into rats under ether anesthesia. For the moderately or severely hyponatremic groups, dDAVP was injected continuously at rates of 0.3 or 0.7 ng/h, respectively.…”