Aß dissociation by pectolinarin may counteract against Aß-induced synaptic dysfunction and memory impairment.

Alzheimer's disease (AD) is a degenerative brain disorder characterised by various neurological symptoms, including memory impairment and mood disorders, associated with the abnormal accumulation of amyloid b(Aß) and tau proteins in the brain. There is still no definitive treatment available for AD, and the Aß antibody drugs, which are expected to be approved by the FDA, have many limitations. Therefore, there is an urgent need to develop low-molecular-weight therapeutic agents for the management of AD. In this study, we investigated whether pectolinarin, a flavonoid, regulates Aß aggregation and Aß-induced toxicity. Pectolinarin demonstrated concentration-dependent inhibition of Aß aggregation and had the ability to break down pre-formed Aß aggregates, thereby reducing their neurotoxicity. Furthermore, pectolinarin suppressed Aß aggregates-induced reduction in long-term potentiation (LTP) in the hippocampus. Oral administration of pectolinarin in experimental animals inhibited memory impairment and LTP deficits induced by Aß injection in the hippocampus. These results indicate that pectolinarin may reduce toxic Aß species and Aß-induced memory impairments and synaptic dysfunction.

Valproic acid increases NO production via the SH-PTP1-CDK5-eNOS-Ser(116) signaling cascade in endothelial cells and mice.

Valproic acid (VPA) with its inhibitory activity of histone deacetylase has been used in the treatment of epilepsy and bipolar disorder associated with cerebrovascular dysfunction. Because nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays a role in the maintenance of vascular function, NO is likely to mediate VPA׳s drug effect, but its effect on NO production remains controversial. We investigated whether and how VPA regulates NO production in bovine aortic endothelial cells (BAECs) and mice. VPA increased NO production in BAECs, which was accompanied by a decrease in phosphorylation of eNOS at serine 116 (eNOS-Ser(116)) and cyclin-dependent kinase 5 at tyrosine 15 (CDK5-Tyr(15)). Ectopic expression of p25, a CDK5 activator, restored the VPA-inhibited eNOS-Ser(116) phosphorylation. In silico analysis revealed that the CDK5-Tyr(15) residue might be a substrate for SH2 domain-containing protein tyrosine phosphatase 1 (SH-PTP1), and CDK5 actually interacted with SH-PTP1. VPA increased SH-PTP1 expression and its activity. Stibogluconate, a specific SH-PTP1 inhibitor, reversed the VPA-inhibited phosphorylation of CDK5-Tyr(15) and eNOS-Ser(116). Knockdown of SH-PTP1 using small interfering RNA also reversed all the observed effects of VPA. Finally, both serum NO level and acetylcholine-induced aortic relaxation increased in VPA-medicated male mice. These increases were accompanied by increased SH-PTP1 expression and decreased phosphorylation of CDK5-Tyr(15) and eNOS-Ser(116) in mouse aortas. In conclusion, VPA increases NO production by inhibiting the CDK5-Tyr(15)-eNOS-Ser(116) phosphorylation axis; this process is mediated by SH-PTP1. VPA may be useful in the treatment of NO-related cerebrocardiovascular diseases.