Suppression of Angiotensin-(1–7) on the Disruption of Blood-Brain Barrier in Rat of Brain Glioma

Abstract

Glioblastoma multiforme (GBM) is the most primary brain tumor, specially characterized with the damage of blood-brain barrier (BBB). The Ang-(1-7) was proven to have an inhibitory effect on glioblastoma growth. However, its role on blood-brain barrier (BBB) and the underlying molecular mechanism remains unclear. In this study, Ang-(1-7) significantly relieved the damage of blood-brain barrier in rats with intracranial U87 gliomas as evaluated by magnetic resonance imaging (MRI). Furthermore, its treatment attenuated BBB permeability, tumor growth and edema formation. Similarly, Ang-(1-7) also decreased U87 glioma cells barrier permeability in vitro. Further analysis showed that Ang-(1-7) could effectively restore tight junction protein (claudin-5 and ZO-1) expression levels both in rats and U87 glioma cells by affecting the activation of JNK pathway. SP600125, an inhibitor of JNK, significantly enhanced the expression of Claudin-5 and ZO-1, and decreased the disruption of BBB and enhanced the efficiency of Ang-(1-7) in glioma rats. Taken together, this study demonstrated a protective role of Ang-(1-7) in glioma-induced blood-brain barrier damage by regulating tight junction protein expression. Accordingly, Ang-(1-7) may become a promising therapeutic agent against glioma.

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“…Studies have shown that JNK inhibitors reduce MMP-9 expression, and increase the expression of TJ proteins (ZO-1, claudin-5, occludin), thereby preventing BBB destruction. [148][149][150] Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) Signaling Pathway JAK is a non-receptor tyrosine protein kinase (PTK) the substrate of which is STAT. JAK is rapidly recruited and activated by cell surface receptors (eg, interferons, interleukins, and growth factors).…”

“…Studies have shown that JNK inhibitors reduce MMP-9 expression, and increase the expression of TJ proteins (ZO-1, claudin-5, occludin), thereby preventing BBB destruction. 148 – 150 …”

Cyclic angiotensin-(1-7) contributes to rehabilitation of animal performance in a rat model of cerebral stroke

“…Therefore it can not be excluded that cAng-(1-7) passes the BBB early after the stroke induction. Intracerebrally administered Ang- (1)(2)(3)(4)(5)(6)(7) exerts protective effects on the BBB integrity, which may contribute to recovery after cerebral stroke, by regulating the tight junction protein expression [30,48]. Restoration of BBB integrity importantly contributes to reducing stroke-related neurological damage [2].…”

“…Consistent with difficult delivery across the BBB, natural Ang-(1-7) has been administered by intracerebral infusion in many studies [1,18,19,30,33,39,40,48]. In essence, the efficient delivery of peptides across the intact BBB to the brain requires invasive techniques.…”

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“…Regulation of vascular tone, cell proliferation, inflammation [48] Protection of NVU cells in insulin resistance, cardiovascular and renal diseases [49,50] Reducing anxiety Modifying the production of corticotropin-releasing hormone in the hypothalamus [52] Decreasing the production of free radicals Initiation of redox signal transduction [53] Modifying the expression of tight junction proteins (claudin-5, ZO1) Reducing the expression of matrix metalloproteinase MMP-9 [54,55] Stimulation of ATP production Preventing mitochondrial fragmentation [56] AT IV Protecting brain cells from ischemia, reducing memory deficit [49,50,57,58] Inhibiting the catalytic activity of IRAP Modifying the glucose transport into cells [59] Inhibition of cysteine aminopeptidase (improving learning and memorization) Anticonvulsant and antiepileptic action Control over the cerebral vascular tone [59,60] Accumulation of endogenous oxytocin [61]…”