Protective Effect of Isorhynchophylline Against β-Amyloid-Induced Neurotoxicity in PC12 Cells

Abstract

Beta-amyloid peptide (Aβ), a major protein component of senile plaques, has been considered as a critical cause in the pathogenesis of Alzheimer's disease (AD). Modulation of the Aβ-induced neurotoxicity has emerged as a possible therapeutic approach to ameliorate the onset and progression of AD. The present study aimed to evaluate the protective effect of isorhynchophylline, an oxindole alkaloid isolated from a Chinese herb Uncaria rhynchophylla, on Aβ-induced neurotoxicity in cultured rat pheochromocytoma (PC12) cells. The results showed that pretreatment with isorhynchophylline significantly elevated cell viability, decreased the levels of intracellular reactive oxygen species and malondialdehyde, increased the level of glutathione, and stabilized mitochondrial membrane potential in Aβ(25-35)-treated PC12 cells. In addition, isorhynchophylline significantly suppressed the formation of DNA fragmentation and the activity of caspase-3 and moderated the ratio of Bcl-2/Bax. These results indicate that isorhynchophylline exerts a neuroprotective effect against Aβ(25-35)-induced neurotoxicity in PC12 cells, at least in part, via inhibiting oxidative stress and suppressing the mitochondrial pathway of cellular apoptosis.

Role of amyloid β in the induction of lipolysis and secretion of adipokines from human adipose tissue

“…Ab [25][26][27][28][29][30][31][32][33][34][35] has no effect on glycerol release at 2, 6, 12 h (data not shown). H89, a well-recognized inhibitor of PKA 26 partially inhibited Ab 25-35 induced glycerol release (P < 0.05 vs. Ab 25-35 alone).…”

“…H89, a well-recognized inhibitor of PKA 26 partially inhibited Ab 25-35 induced glycerol release (P < 0.05 vs. Ab 25-35 alone). Similarly, PD98059, an inhibitor of ERK1/2 27 also partially inhibited Ab [25][26][27][28][29][30][31][32][33][34][35] induced glycerol release (P < 0.05 vs. Ab 25-35 alone).…”

“…Ab [25][26][27][28][29][30][31][32][33][34][35] is the main functional domain of the Ab molecule that is required for neurotoxic effects. 28 We found that Ab [25][26][27][28][29][30][31][32][33][34][35] can induce lipolysis in cultured adipose tissue in a manner that appeared partially dependent on PKA and ERK1/2-dependent signaling pathways. Lipolysis for the provisions of fatty acids as a fuel for other tissues is a unique function of adipose.…”

“…30 Similarly, chronic low-grade elevations of IL-6 in adipose tissue are posited to directly contribute to insulin resistance. [31][32] Given the previous associations between adipose tissue APP and Ab in rodent models of obesity, the induction of leptin and IL-6 secretion by Ab [25][26][27][28][29][30][31][32][33][34][35] may indicate that Ab might contribute to adipose tissue inflammation and promote insulin resistance. It should be noted that in the present study we assessed the impact of aggregated Ab on cultured human adipose tissue.…”

“…Alternative peptides can be derived from cleavage at the C-terminus including Ab , Ab , Ab and Ab [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] . Ab [25][26][27][28][29][30][31][32][33][34][35] is derived from cleavage at both termini, and is considered the core functional domain of Ab peptides. 3 Although much of the study of APP and Ab has focused on changes in the central nervous system during AD pathology, as early as in 1989 Joachim et al 4 reported that APP protein and mRNA are expressed in other tissues besides brain including adipose tissue, heart, muscle, kidney, liver, spleen, skin and intestine.…”