ABSTRACT
Fluoxetine, an anti-depressant drug, has recently been shown to provide neuroprotection in central nervous system injury, but its roles in subarachnoid hemorrhage (SAH) remain unclear. In this study, we aimed to evaluate whether fluoxetine attenuates early brain injury (EBI) after SAH. We demonstrated that intraperitoneal injection of fluoxetine (10 mg/kg per day) significantly attenuated brain edema and blood-brain barrier (BBB) disruption, microglial activation, and neuronal apoptosis in EBI after experimental SAH, as evidenced by the reduction of brain water content and Evans blue dye extravasation, prevention of disruption of the tight junction proteins zonula occludens-1, claudin-5, and occludin, a decrease of cells staining positive for Iba-1, ED-1, and TUNEL and a decline in IL-1β, IL-6, TNF-α, MDA, 3-nitrotyrosine, and 8-OHDG levels. Moreover, fluoxetine significantly improved the neurological deficits of EBI and long-term sensorimotor behavioral deficits following SAH in a rat model. These results indicated that fluoxetine has a neuroprotective effect after experimental SAH.
Subject(s)
Animals , Male , Rats , Apoptosis , Blood-Brain Barrier , Brain Edema , Drug Therapy , Cytokines , Genetics , Metabolism , Disease Models, Animal , Fluoxetine , Pharmacology , Therapeutic Uses , In Situ Nick-End Labeling , Neuroprotective Agents , Pharmacology , Therapeutic Uses , Pain Measurement , Psychomotor Performance , RNA, Messenger , Metabolism , Rats, Sprague-Dawley , Subarachnoid Hemorrhage , Drug Therapy , Pathology , Time Factors , Vasospasm, Intracranial , Drug TherapyABSTRACT
<p><b>BACKGROUND</b>Enhanced and prolonged expression of connective tissue growth factor (CTGF) is associated with kidney fibrosis. Parathyroid hormone (PTH) is involved in the genesis of disturbed calcium/phosphate metabolism and ostitis fibrosa in renal failure. PTH activated mitogen-activated protein kinase (MAPK) signaling pathway is present in renal tubular cells. The aim of this study was to identify the mechanism how the signal is transduced to result in extracellular signal-regulated protein kinase (ERK) activation, leading to upregulation of CTGF.</p><p><b>METHODS</b>The levels of CTGF mRNA and protein in human kidney proximal tubular cells (HK-2) treated with PTH in the presence or absence of the MAPK inhibitor PD98059 were analyzed by quantitative real-time polymerase chain reaction (RT-PCR) and immunoblotting assay. The activation of the CTGF promoter in HK-2 cells was determined by the dual-luciferase assay. The effects of the protein kinase A (PKA) activator 8-Br-cAMP and protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) on MAPK phosphorylation, and the effects of the PKA inhibitor H89 and PKC inhibitor calphostin C on MAPK phosphorylation and CTGF expression were detected by immunoblotting assay.</p><p><b>RESULTS</b>PD98059 inhibited the PTH stimulated expression of CTGF, which strongly suggested that the MAPK signaling pathway plays an important role in the PTH-induced CTGF upregulation in renal tubular cells. A PKA activator as well as PKC activators induced MAPK phosphorylation, and both PKA and PKC inhibitors antagonized PTH-induced MAPK phosphorylation and CTGF expression.</p><p><b>CONCLUSION</b>CTGF expression is upregulated by PTH through a PKC/PKA-ERK-dependent pathway.</p>
Subject(s)
Humans , Cells, Cultured , Connective Tissue Growth Factor , Genetics , Physiology , Cyclic AMP-Dependent Protein Kinases , Physiology , Extracellular Signal-Regulated MAP Kinases , Physiology , Fibrosis , Flavonoids , Pharmacology , Kidney Tubules, Proximal , Metabolism , Pathology , MAP Kinase Signaling System , Mitogen-Activated Protein Kinases , Physiology , Parathyroid Hormone , Pharmacology , Phosphorylation , Protein Kinase C , PhysiologyABSTRACT
<p><b>OBJECTIVE</b>To investigate the clinical and pathological characteristics of patients with clinically presumed hypertensive nephrosclerosis (HN).</p><p><b>METHODS</b>Clinical data and renal biopsy results were obtained in 63 patients diagnosed clinically as HN (primary hypertension plus renal injury).</p><p><b>RESULTS</b>HN was confirmed by biopsy in 47 out of 63 patients (74.6%, 12 malignant nephrosclerosis and 35 benign nephrosclerosis). Primary nephritis (PN) was diagnosed by biopsy in 10 patients (7 IgA nephropathy, 2 mesangial proliferative nephritis, 1 chronic interstitial nephritis) and focal and segmental glomerulosclerosis (FSGS) in 6 patients. Blood pressure, body mass index, GFR and blood lipids were similar among groups. HN patients were related to higher age, more frequent family history of hypertension, longer hypertension duration, higher left ventricular mass index, lower serum creatinine and lower incidence of microscopic hematuria. Most patients with malignant nephrosclerosis and FSGS patients showed grades III and IV retinopathy.</p><p><b>CONCLUSION</b>Our results show that HN was misdiagnosed in nearly 25% patients in this cohort. Since the clinical features are similar between HN, PN and FSGS, renal biopsy is needed to establish the diagnosis of HN.</p>