Isorhynchophylline Treatment Improves the Amyloid-β-Induced Cognitive Impairment in Rats via Inhibition of Neuronal Apoptosis and Tau Protein Hyperphosphorylation

Abstract

The progressive accumulation of amyloid-β (Aβ) in the form of senile plaques has been recognized as a key causative factor leading to the cognitive deficits seen in Alzheimer's disease (AD). Recent evidence indicates that Aβ induces neurotoxicity in the primary neuronal cultures as well as in the brain. Previously, we have demonstrated that isorhynchophylline (IRN), the major chemical ingredient of Uncaria rhynchophylla, possessed potent neuroprotective effects. In the present study, we aimed to investigate the effect of IRN on cognitive function, neuronal apoptosis, and tau protein hyperphosphorylation in the hippocampus of the Aβ25-35-treated rats and to elucidate its action mechanisms. We showed that Aβ25-35 injection caused spatial memory impairment, neuronal apoptosis, and tau protein hyperphosphorylation. Treatment with IRN (20 or 40 mg/kg) for 21 days could significantly ameliorate the cognitive deficits induced by Aβ25-35 in the rats. In addition, IRN attenuated the Aβ25-35-induced neuronal apoptosis in hippocampus by down-regulating the protein and mRNA levels of the ratio of Bcl-2/Bax, cleaved caspase-3 and caspase-9, as well as suppressing the tau protein hyperphosphorylation at the Ser396, Ser404, and Thr205 sites. Mechanistic study showed that IRN could inhibit the glycogen synthase kinase 3β (GSK-3β) activity, and activate the phosphorylation of phosphatidylinositol 3-kinase (PI3K) substrate Akt. These results indicate that down-regulation of GSK-3β activity and activation of PI3K/Akt signaling pathway are intimately involved in the neuroprotection of IRN. The experimental findings provide further evidence to affirm the potential of IRN as a worthy candidate for further development into a therapeutic agent for AD and other tau pathology-related neurodegenerative diseases.

Association of traditional Chinese medicine therapy and the risk of dementia in patients with hypertension: a nationwide population-based cohort study

“…Reducing the amount of beta-amyloid protein (Aβ) and tau protein in the brain and modulating Aβ toxicity, including inflammatory response, oxidative stress, and neuronal apoptosis, have been considered the most promising therapeutic strategies available for controlling the progression of dementia [23, 24]. …”

Medicinal uses, phytochemistry and pharmacology of the genus Uncaria

“…Among Uncaria species, U. tomentosa was considered as effective antitumor candidate to inhibit cancer cells growth, such as HL-60 (leukemia) (Cheng et al, 2007;Bacher et al, 2006), MCF7 and MT-3 (breast) (Riva et al, 2001;Sun et al, 2012a;Pilarski et al, 2010;García Giménez et al, 2010), (Dreifuss et al, 2013) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 Xian et al, 2014Xian et al, et al, 2007. The correlations between pharmacological properties of U. tomentosa and active compounds revealed that oxindole alkaloids and triterpenes are major bioactive constituents.…”

Honokiol improves learning and memory impairments induced by scopolamine in mice

“…The doses of the honokiol were selected with reference to previous studies (Qu et al, 2012;Vavilala et al, 2013). Donepezil hydrochloride was used as the positive control (Xian et al, 2014). Honokiol was dissolved in sterile saline containing 10% dimethyl sulfoxide (DMSO), while SCOP and donepezil were dissolved in normal sterile saline.…”

“…The Morris water maze test was conducted as described in our previous publication (Xian et al, 2014), with minor modifications. The experimental apparatus (Water Mazes, TSE systems, Germany) consisted of a blank circular water tank (100 cm in diameter, 35 cm in height), containing water (23 71 1C) to a depth of 15.5 cm, which was rendered opaque by adding ink.…”