A novel anti-fibrotic agent, baicalein, for the treatment of myocardial fibrosis in spontaneously hypertensive rats.

Myocardial interstitial fibrosis causes left ventricular stiffness and diastolic dysfunction. Despite its clinical significance, treatment options are limited. The flavonoid baicalein, extracted from roots of a Chinese medicinal plant, Scutellaria baicalensis Georgi was shown to inhibit liver fibrosis. This study sought to investigate whether chronic treatment with baicalein could attenuate myocardial fibrosis in spontaneously hypertensive rats (SHR). SHR were treated daily with baicalein while the control group received vehicle. At the end of study, SHR control group developed significant myocardial fibrosis that was attenuated by baicalein treatment for 4 and 12 weeks. Rats treated with baicalein were protected against an increase in heart to body weight ratio, plasma level of brain natriuretic peptides, intraventricular septum thickness, myocardial collagen volume of left ventricle (all P<0.05, respectively). The antifibrotic effects of baicalein were further illustrated by the suppressed expression of left ventricle pro-collagens I and III accompanied by the decreased expression of 12-lipoxygenase, and by reduced expression and activity of matrix metallopeptidase 9 and extracellular signal-regulated kinases. The present results show for the first time that baicalein can inhibit cardiac fibrosis in hypertensive rats.

Astrocytic transactivation by alpha2A-adrenergic and 5-HT2B serotonergic signaling.

EGF receptor transactivation has been known for more than ten years. It is a signal pathway in which a G-protein-coupled receptor (GPCR) signal leads to release of a growth factor, which in turn activates the EGF receptor-tyrosine kinase in the same or adjacent cells. Astrocytes express a number of GPCRs and play key roles in brain function. Astrocytic transactivation is of special interest, since its autocrine effect may regulate gene expression and alter cell functions in the cells themselves and its paracrine effect may provide additional opportunities for cross-talk between astrocytes and their neighbors, such as neurons. The signal pathways of EGF transactivation are complicated. This does not only apply to the pathways leading to shedding of growth factor(s), but also to the downstream signal pathways of the EGF receptor, i.e., MAPK and PI3K. The latter may vary according to the type of growth factor released, the sites of tyrosine phosphorylation on the EGF receptor, and the duration of the phosphorylation. Using primary cell cultures we have found that dexmedetomidine, a specific alpha(2)-adrenergic receptor, induced shedding of HB-EGF from astrocytes, which in turn transactivated EGF receptors and stimulated astrocytic c-Fos and FosB expression. At the same time released HB-EGF protected neurons from injury caused by H(2)O(2). We have also confirmed dexmedetomidine transactivation in the brain in vivo. EGF transactivation by 5-HT(2B) receptor stimulation was responsible for up-regulation of cPLA(2) in astrocytes by fluoxetine, an antidepressant and inhibitor of the serotonin transporter, which also is a specific 5-HT(2B) agonist.

Baicalein and Wogonin inhibit collagen deposition in SHR and WKY cardiac fibroblast cultures.

In order to demonstrate the potential therapeutic effect of two flavonoids, Baicalein and Wogonin, on suppression of pathological myocardial fibrosis in hypertension, we investigated their in vitro effects on collagen expression in primary cultured cardiac fibroblasts isolated from neonatal normotensive (WKY) and hypertensive (SHR) rats. Our results showed that over-expression of collagen mRNA and protein induced in cardiac fibroblasts by angiotensin (AngII) could be attenuated significantly by both flavonoids at an optimal dosage (30 microM; P < 0.01). Results of immunoblots showed that expression of 12-LO level, p-ERK/ ERK ratio and MMP-9 in AngII|-stimulated SHR cardiac fibroblasts were significantly down-regulated by both flavonoids. Our results show that both Baicalein and Wogonin can suppress collagen deposition in AngII-stimulated SHR and WKY cardiac fibroblasts.

Up-regulation of 5-HT2B receptor density and receptor-mediated glycogenolysis in mouse astrocytes by long-term fluoxetine administration.

The effects were studied of short-term (1 week) versus long-term (2-3 weeks) fluoxetine treatment of primary cultures of mouse astrocytes, differentiated by treatment with dibutyryl cyclic AMP. From previous experiments it is known that acute treatment with fluoxetine stimulates glycogenolysis and increases free cytosolic Ca2+ concentration ([Ca2+]i]) in these cultures, whereas short-term (one week) treatment with 10 microM down-regulates the effects on glycogen and [Ca2+]i, when fluoxetine administration is renewed (or when serotonin is administered). Moreover, antagonist studies have shown that these responses are evoked by activation of a 5-HT2, receptor that is different from the 5-HT2A receptor and therefore at that time tentatively were interpreted as being exerted on 5-HT2C receptors. In the present study the cultures were found by RT-PCR to express mRNA for 5-HT2A and 5-HT2B receptors, but not for the 5-HT2C receptor, identifying the 5-HT2 receptor activated by fluoxetine as the 5-HT2B receptor, the most recently cloned 5-Ht2 receptor and a 5-HT receptor known to be more abundant in human, than in rodent, brain. Both short-term and long-term treatment with fluoxetine increased the specific binding of [3H]mesulergine, a ligand for alL three 5-HT2 receptors. Long-term treatment with fluoxetine caused an agonist-induced up-regulation of the glycogenolytic response to renewed administration of fluoxetine, whereas short-term treatment abolished the fluoxetine-induced hydrolysis of glycogen. Thus, during a treatment period similar to that required for fluoxetine's clinical response to occur, 5-HT2B-mediated effects are initially down-regulated and subsequently up-regulated.