Endothelin-1 (ET-1) is a neuroactive peptide produced by neurons, reactive astrocytes, and endothelial cells in the brain. Elevated levels of ET-1 have been detected in the post-mortem brains of individuals with Alzheimer's disease (AD). We have previously demonstrated that overexpression of astrocytic ET-1 exacerbates memory deficits in aged mice or in APPK670/M671 mutant mice. However, the effects of ET-1 on neuronal dysfunction remain elusive. ET-1 has been reported to mediate superoxide formation in the vascular system via NADPH oxidase (NOX) and to regulate the actin cytoskeleton of cancer cell lines via the cofilin pathway. Interestingly, oxidative stress and cofilin activation were both reported to mediate one of the AD histopathologies, cofilin rod formation in neurons. This raises the possibility that ET-1 mediates neurodegeneration via oxidative stress- or cofilin activation-driven cofilin rod formation. Here, we demonstrate that exposure to 100 nm ET-1 or to a selective ET type B receptor (ETB) agonist (IRL1620) induces cofilin rod formation in dendrites of primary hippocampal neurons, accompanied by a loss of distal dendrites and a reduction in dendritic length. The 100 nm IRL1620 exposure induced superoxide formation and cofilin activation, which were abolished by pretreatment with a NOX inhibitor (5 μm VAS2870). Moreover, IRL1620-induced cofilin rod formation was partially abolished by pretreatment with a calcineurin inhibitor (100 nm FK506), which suppressed cofilin activation. In conclusion, our findings suggest a role for ETB in neurodegeneration by promoting cofilin rod formation and dendritic loss via NOX-driven superoxide formation and cofilin activation.
Piper sarmentosum is a tropical plant in Southeast Asia known for its traditional use in curing various ailments including hypertension. Previous research works have provided evidence for the herb's antihypertensive property. However, the exact mechanisms involved are still in question. The present study investigated the effects of Piper sarmentosum leaves aqueous extract (PSAE) treatment on vascular endothelin system in spontaneously hypertensive rats (SHRs). Four groups of SHRs were treated for 28 consecutive days, with negative and positive control groups receiving distilled water and 3 mg/kg perindopril, respectively. Another two groups are the treatment groups, which received PSAE and combination of 1.5 mg/kg perindopril and PSAE. Weekly measurements of blood pressure showed that PSAE significantly reduced the systolic, diastolic, and mean arterial pressures (P < 0.05) of the rats. PSAE also increased mesenteric artery nitric oxide (NO) level (P < 0.05) and reduced endothelin-1 (ET-1) level (P < 0.05) in the treatment groups. Our results demonstrate that oral administration of PSAE reduced blood pressure in SHRs by reducing the ET-1 level while increasing NO production.