The Neurovascular Protective Effects of Huperzine A on D-Galactose-Induced Inflammatory Damage in the Rat Hippocampus

Abstract

Background: Chronic administration of <smlcap>D</smlcap>-galactose (<smlcap>D</smlcap>-gal) results in oxidative stress and chronic inflammatory aging. Age-related changes in the brain result in neurovascular damage and blood-brain barrier (BBB) dysfunction. However, little is known regarding <smlcap>D</smlcap>-gal-induced neurovascular damage, as well as the protective effects of huperzine A. Objective: The purpose of this study was to utilize a<smlcap> D</smlcap>-gal-induced rat model to investigate the activation of neurovascular inflammatory damage and apoptosis in the rat hippocampus and to understand whether huperzine A alleviates <smlcap>D</smlcap>-gal-induced neuronal and vascular inflammatory injury. Methods: Aging rats were treated with <smlcap>D</smlcap>-gal (300 mg/kg s.c. for 8 weeks), were coadministered <smlcap>D</smlcap>-gal and huperzine A (<smlcap>D</smlcap>-gal 300 mg/kg and huperzine A 0.1 mg/kg s.c. for 8 weeks) or served as the saline-treated control group rats (same volume of saline given subcutaneously for 8 weeks). Changes in hippocampal morphology and biomarkers of inflammatory damage were analyzed. Results: Our study revealed that chronic administration of <smlcap>D</smlcap>-gal resulted in the activation of glia and vascular endothelial cells and upregulation of mRNA and protein levels of cell-associated adhesion molecules and inflammatory cytokines via nuclear factor (NF)-κB inhibitor degradation and NF-κB nuclear translocation. The inflammatory injury caused significant BBB dysfunction, decreased density of tight junctions (TJs) and apoptosis in the rat hippocampus. Coadministration of huperzine A not only markedly inhibited the <smlcap>D</smlcap>-gal-induced increase in acetylcholinesterase (AChE) activity, but also alleviated <smlcap>D</smlcap>-gal-induced neurovascular damage by inhibiting <smlcap>D</smlcap>-gal-induced NF-κB activation, improving cerebrovascular function and suppressing the <smlcap>D</smlcap>-gal-induced decrease in the density and protein levels of TJs and cell apoptosis. Conclusions: Our findings provided evidence that <smlcap>D</smlcap>-gal induced a proinflammatory phenotype mediated by NF-κB in the rat hippocampus. Moreover, huperzine A suppressed <smlcap>D</smlcap>-gal-induced neurovascular damage and BBB dysfunction, partly by preventing NF-κB nuclear translocation. The inhibiting effect of huperzine A on AChE activity might play an important role in attenuating <smlcap>D</smlcap>-gal-induced inflammatory damage.

The Genus Diphasiastrum and Its Lycopodium Alkaloids

“…Annotine isolated from L. annotinum was shown to affect the maturation of dendritic cells and direct T cells toward a Th2/Treg phenotype in a recent study [32] and huperzine A (l " Fig. 2) has also been shown to affect inflammatory responses [33][34][35][36][37]. The dimers complanadines A, B, D, and E (45-48) from D. complanatum were reported to induce secretion of neurotropic factors from human astrocytoma cells; unfortunately the purity of the alkaloids tested was not stated [38,39].…”

Quantitative and Systems Pharmacology 3. Network-Based Identification of New Targets for Natural Products Enables Potential Uses in Aging-Associated Disorders

“…Oxidative stress accelerates the chronic inflammatory process during aging and aging-associated diseases (Cannizzo et al, 2011 ). A previous study showed that HupA alleviated oxidative stress-induced inflammatory damage in aging rat (Ruan et al, 2014 ).…”

Neuroprotective Effect of Huperzine A on d-Galactose-Induced Hearing Dysfunction

“…[27][28][29][30] In addition, huperzine A may protect against diverse neurodegenerative diseases by blocking N-methyl-D-aspartate receptors 31 and by inhibiting D-galinduced neuroinflammation via regulating the NF-kB signaling pathway. 32 Huperzine A can also upregulate the cholinergic anti-inflammatory pathway and inhibit immunosenescence and age-related disorders, such as Alzheimer disease, by inhibiting AChE activity. [21][22][23][24] It has also been demonstrated that huperzine A has the potential to attenuate D-gal-induced inflammation-associated aging in the rat liver by counteracting hepatic inflammation and replicative senescence.…”