Matrine improves cognitive impairment and modulates the balance of Th17/Treg cytokines in a rat model of A β1-42 -induced Alzheimer’s disease

Abstract

Matrine (MAT) has been reported for its anti-inflammatory and neuroprotective effects. However, little is known about its effects on Th17/Treg cytokines and cognitive impairment in Alzheimer's disease (AD). In the present study, we injected Aβ1-42 to the hippocampus of the rat to induce AD. Three groups of the AD rats were treated with MAT (25, 100 or 200 mg/kg/day, respectively) by intraperitoneal injection for 5 weeks. Levels of Th17 cell cytokines [interleukin (IL)-17A and IL-23] and regulatory T (Treg) cell cytokines [transforming growth factor β (TGF-β) and IL-35] in homogenates of the brain cortex and hippocampus were measured using enzyme-linked immunosorbent assay (ELISA) kits. The mRNA expressions of Th17 cell specific transcription factor RORγt and Treg cell specific transcription factor Foxp3 in the brain cortex and hippocampus were quantified by real-time RT-PCR. Learning and memory ability of the rats were evaluated by Morris water maze test and novel object recognition test. ELISA detections showed the AD rats had increased levels of IL-17A and IL-23 as well as decreased levels of TGF-β and IL-35. Matrine (100 and 200 mg/kg/day) significantly reversed the alternations of Th17/Treg cytokines induced by Aβ1-42 injection, decreased RORγt mRNA expression, increased Foxp3 mRNA expression and improved the learning and memory ability in the AD rats. The findings demonstrated that the AD rats had imbalance of Th17/Treg cytokines in the brain. MAT could dose-dependently restore the balance of Th17/Treg cytokines and attenuate the cognitive impairment in AD rats.

Neutralization of IL‐17 rescues amyloid‐β‐induced neuroinflammation and memory impairment

“…administration ameliorated Aβ‐like symptoms (in terms of olfactory dysfunction, spatial and working memory) both after 7 and 14 days, similar to that observed after a double IL‐17Ab IN administration on days 5 and 12. The difference in terms of time of administration is justified by earlier observations that found a significant increase of Th17 cytokines following 7 days from Aβ injection (Zhang et al, ; Zhang et al, ). Moreover, very robust effects were observed when the Ab was administered at dose of 1 μg·μl −1 , compared with the isotype Control or Ab itself, consistent with previous in vivo reports (Fischer et al, ; Mi et al, ; Szabo et al, ).…”

“…Increased levels of Th17 transcription factor RORγt, in addition to IL-17 and IL-22, have been found in the brains of animal models of AD (Zhang, Ke, Liu, Qiu, & Peng, 2013;Zhang, Liu, Sun, & Yin, 2015) and the increase of Th17/IL-17A axis is sustained by Aβ-induced oxidative stress (Solleiro-Villavicencio & Rivas-Arancibia, 2017). Furthermore, Zenaro et al (2015) showed a role for neutrophils in AD-like pathogenesis and cognitive impairment through the release of neutrophil extracellular traps and IL-17 into the brain, suggesting that the inhibition of neutrophil trafficking and related neuro-inflammatory onset may be beneficial in this pathology.…”

Interleukin-17A: The Key Cytokine in Neurodegenerative Diseases

“…In 5XFAD mice, another animal model of AD, the production of IL-17A is decreased in the gut-residing immune cells (Saksida et al, 2018 ). In another animal models of AD including hAPP mice, 3xTg-AD mice, Mo/Hu APPswe PS1dE9 mice and Aβ1–42-Induced AD rat model, the level of IL-17A shows a significant upregulation compared with wild type mice (Jin et al, 2008 ; Zhang et al, 2013 ; Zhang Y. et al, 2015 ; Chen et al, 2015 , 2019 ; Yang et al, 2015 ; St-Amour et al, 2019 ). In MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) treaded mouse and MPP+ (1-methyl-4-phenylpyridinium) treated rats (animal models of PD), the levels of IL-17A are upregulated in the substantia nigra, spleen, serum, and mesenteric lymph nodes.…”

Matrine Exerts Antidepressant-Like Effects on Mice: Role of the Hippocampal PI3K/Akt/mTOR Signaling

“…Matrine was considered in our study because of knowledge that it had promoting effects on the PI3K/Akt/mTOR signaling in brain ( Liu et al , 2017 ), while mTOR is closely involved in the pathophysiology of depression ( Abelaira et al , 2014 ). Besides, previous studies have demonstrated that matrine has protecting and improving effects on neuropathic pain, Alzheimer’s disease, and Parkinson’s disease ( Zhang et al , 2015 ; Gong et al , 2016 ; Meng et al , 2017 ). These reports may also imply the antidepressant-like actions of matrine, as these neurological disorders are always accompanied with depression ( Li et al , 2014 ; Goto et al, 2018 ; Laumet et al , 2017 ; Sampath et al , 2017 ).…”

“…For example, Gong et al reported that matrine had neuroprotective effects on a mouse model of vincristine-induced neuropathic pain ( Gong et al , 2016 ). Zhang et al showed that matrine improved cognitive impairments in a rat model of Alzheimer’s disease ( Zhang et al , 2015 ). Meng et al showed that matrine also had neuroprotective effects against MPTP-induced Parkinson’s disease ( Meng et al , 2017 ).…”