minocycline and Hyponatremia

Overly rapid correction of chronic hyponatremia can cause osmotic demyelination syndrome (ODS). Minocycline protects ODS associated with overly rapid correction of chronic hyponatremia with hypertonic saline infusion in rats. In clinical practice, inadvertent rapid correction frequently occurs due to water diuresis, when vasopressin action suddenly ceases. In addition, vasopressin receptor antagonists have been applied to treat hyponatremia. Here the susceptibility to and pathology of ODS were evaluated using rat models developed to represent rapid correction of chronic hyponatremia in the clinical setting. The protective effect of minocycline against ODS was assessed. Chronic hyponatremia was rapidly corrected by 1 (T1) or 10 mg/kg (T10) of tolvaptan, removal of desmopressin infusion pumps (RP), or administration of hypertonic saline. The severity of neurological impairment in the T1 group was significantly milder than in other groups and brain hemorrhage was found only in the T10 and desmopressin infusion removal groups. Minocycline inhibited demyelination in the T1 group. Further, immunohistochemistry showed loss of aquaporin-4 (AQP4) in astrocytes before demyelination developed. Interestingly, serum AQP4 levels were associated with neurological impairments. Thus, minocycline can prevent ODS caused by overly rapid correction of hyponatremia due to water diuresis associated with vasopressin action suppression. Increased serum AQP4 levels may be a predictive marker for ODS.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Aquaporin 4; Astrocytes; Behavior, Animal; Benzazepines; Biomarkers; Brain; Chemokines; Cytokines; Cytoprotection; Deamino Arginine Vasopressin; Demyelinating Diseases; Disease Models, Animal; Diuresis; Hyponatremia; Intracranial Hemorrhages; Male; Matrix Metalloproteinases; Minocycline; Neuroprotective Agents; Osmosis; Rats, Sprague-Dawley; Saline Solution, Hypertonic; Sodium; Therapeutics; Time Factors; Tolvaptan; Water-Electrolyte Balance

Binding of vasopressin to its type 2 receptor in renal collecting ducts induces cAMP signaling, transcription and translocation of aquaporin (AQP)2 water channels to the plasma membrane, and water reabsorption from the prourine. Demeclocycline is currently used to treat hyponatremia in patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Demeclocycline's mechanism of action, which is poorly understood, is studied here. In mouse cortical collecting duct (mpkCCD) cells, which exhibit deamino-8-D-arginine vasopressin (dDAVP)-dependent expression of endogenous AQP2, demeclocycline decreased AQP2 abundance and gene transcription but not its protein stability. Demeclocycline did not affect vasopressin type 2 receptor localization but decreased dDAVP-induced cAMP generation and the abundance of adenylate cyclase 3 and 5/6. The addition of exogenous cAMP partially corrected the demeclocycline effect. As in patients, demeclocycline increased urine volume, decreased urine osmolality, and reverted hyponatremia in an SIADH rat model. AQP2 and adenylate cyclase 5/6 abundances were reduced in the inner medulla but increased in the cortex and outer medulla, in the absence of any sign of toxicity. In conclusion, our in vitro and in vivo data indicate that demeclocycline mainly attenuates hyponatremia in SIADH by reducing adenylate cyclase 5/6 expression and, consequently, cAMP generation, AQP2 gene transcription, and AQP2 abundance in the renal inner medulla, coinciding with a reduced vasopressin escape response in other collecting duct segments.

Topics: Adenylyl Cyclases; Animals; Anti-Bacterial Agents; Aquaporin 2; Cells, Cultured; Cyclic AMP; Deamino Arginine Vasopressin; Demeclocycline; Disease Models, Animal; Hyponatremia; In Vitro Techniques; Inappropriate ADH Syndrome; Kidney Medulla; Male; Mice; Minocycline; Rats; Rats, Wistar; Vasopressins

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-1β, inducible nitric-oxide synthase, and TNF-α), 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.

Topics: Analysis of Variance; Animals; Cells, Cultured; Cytokines; Demyelinating Diseases; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Hyponatremia; Immunohistochemistry; Male; Matrix Metalloproteinases; Microglia; Minocycline; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Osmotic demyelination syndrome is a devastating neurologic condition that occurs after rapid correction of serum sodium in patients with hyponatremia. Pathologic features of this injury include a well-demarcated region of myelin loss, a breakdown of the blood-brain barrier, and infiltration of microglia. The semisynthetic tetracycline minocycline is protective in some animal models of central nervous system injury, including demyelination, suggesting that it may also protect against demyelination resulting from rapid correction of chronic hyponatremia. Using a rat model of osmotic demyelination syndrome, we found that treatment with minocycline significantly decreases brain demyelination, alleviates neurologic manifestations, and reduces mortality associated with rapid correction of hyponatremia. Mechanistically, minocycline decreased the permeability of the blood-brain barrier, inhibited microglial activation, decreased both the expression of IL1α and protein nitrosylation, and reduced the loss of GFAP immunoreactivity. In conclusion, minocycline modifies the course of osmotic demyelination in rats, suggesting its possible therapeutic use in the setting of inadvertent rapid correction of chronic hyponatremia in humans.

Topics: Analysis of Variance; Animals; Blood-Brain Barrier; Demyelinating Diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Fluorescent Antibody Technique; Hyponatremia; Immunohistochemistry; Male; Minocycline; Osmosis; Random Allocation; Rats; Statistics, Nonparametric; Survival Rate

Topics: Animals; Chronic Disease; Demyelinating Diseases; Disease Models, Animal; Humans; Hyponatremia; Minocycline; Osmotic Pressure; Rats; Sodium; Time Factors

Six cases of scrub typhus (tsutsugamushi disease) were reported to the Shizuoka Prefecture Hamamatsu City public health center during the seven years from 2001 to 2007. The content of the clinical record of the five cases were investigated. High serum titers of antibody to Gilliam-type Orientia tsutsugamushi were detected by immunofluorescense assay in most of these patients. Fever, rash, headache and relative bradycardia seen at a high frequency. On peripheral blood smear examination, atypical lymphocytes were detected in 3 cases. Serum electrolyte examination revealed hyponatremia in 4 (80%) patients; SIADH was suspected in one of these cases. All the patients improved promptly following start of therapy with intravenous or oral minocycline.

Topics: Aged; Anti-Bacterial Agents; Antibodies, Bacterial; Biomarkers; Female; Humans; Hyponatremia; Immunoglobulin G; Immunoglobulin M; Japan; Male; Middle Aged; Minocycline; Orientia tsutsugamushi; Retrospective Studies; Scrub Typhus; Serologic Tests; Time Factors; Treatment Outcome