Hao Wang1, Fang Chen2, Yi-Feng Du3, Yan Long2, Miranda N Reed3, Mei Hu2, Vishnu Suppiramaniam3, Hao Hong4, Su-Su Tang5. 1. Department of Pharmacology, Key Laboratory of Neuropsychiatric Diseases, China Pharmaceutical University, Nanjing 210009, China; Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health, Zhejiang University School of Medicine, Hangzhou 310058, China. 2. Department of Pharmacology, Key Laboratory of Neuropsychiatric Diseases, China Pharmaceutical University, Nanjing 210009, China. 3. Department of Drug Discovery and Development, School of Pharmacy, Auburn University, Auburn, AL, USA. 4. Department of Pharmacology, Key Laboratory of Neuropsychiatric Diseases, China Pharmaceutical University, Nanjing 210009, China. Electronic address: honghao@cpu.edu.cn. 5. Department of Pharmacology, Key Laboratory of Neuropsychiatric Diseases, China Pharmaceutical University, Nanjing 210009, China. Electronic address: tang_susu@126.com.
Abstract
AIMS: To investigate restorative effects of the receptor for advanced glycation end products (RAGE)-specific inhibitor FPS-ZM1 on abnormal amyloid β (Aβ) influx across the blood brain-barrier (BBB) and cognitive deficits in db/db mice. METHODS: Aβ influx across the BBB was determined by intra-arterial infusion of 125I-Aβ1-40. Receptor for advanced glycation end products (RAGE), Aβ, NF-κB p65, caspase-3, Bax, Bcl-2, PSD-95 and synaptophysin were assayed by Western blot, immunohistochemistry or RT-PCR. Apoptosis was quantified by TUNEL assay. In vivo hippocampal long term potentiation (LTP) recording, Golgi Staining, Morris water maze (MWM) task and Y-maze test were performed. RESULTS: FPS-ZM1 (1.0 mg/kg i.p.) inhibited Aβ influx across the BBB and expression of RAGE participating in Aβ influx, consequently decreased hippocampal Aβ1-40 and Aβ1-42 in db/db mice. After FPS-ZM1 treatment, NF-κB signaling was inhibited, and neuronal apoptosis was reduced, which revealed by less TUNEL + cells, reduced caspase-3 activity and higher ratio of Bcl-2/Bax. In addition, FPS-ZM1 improved hippocampal plasticity evidenced by enhanced in vivo LTP and the restoration of spine deficit and increased PSD-95 expression in hippocampal neuron. Further studies found that FPS-ZM1 treatment alleviated cognitive deficits shown by better performance in behavioral tests, without significant metabolic effects on blood glucose, insulin and cerebral AGEs. CONCLUSION: Downregulation of abnormal Aβ influx across the BBB by FPS-ZM1 at higher dosage contributes to reduced neuronal apoptosis, improved hippocampal plasticity and cognitive impairment in db/db mice.
AIMS: To investigate restorative effects of the receptor for advanced glycation end products (RAGE)-specific inhibitor FPS-ZM1 on abnormal amyloid β (Aβ) influx across the blood brain-barrier (BBB) and cognitive deficits in db/db mice. METHODS: Aβ influx across the BBB was determined by intra-arterial infusion of 125I-Aβ1-40. Receptor for advanced glycation end products (RAGE), Aβ, NF-κB p65, caspase-3, Bax, Bcl-2, PSD-95 and synaptophysin were assayed by Western blot, immunohistochemistry or RT-PCR. Apoptosis was quantified by TUNEL assay. In vivo hippocampal long term potentiation (LTP) recording, Golgi Staining, Morris water maze (MWM) task and Y-maze test were performed. RESULTS: FPS-ZM1 (1.0 mg/kg i.p.) inhibited Aβ influx across the BBB and expression of RAGE participating in Aβ influx, consequently decreased hippocampal Aβ1-40 and Aβ1-42 in db/db mice. After FPS-ZM1 treatment, NF-κB signaling was inhibited, and neuronal apoptosis was reduced, which revealed by less TUNEL + cells, reduced caspase-3 activity and higher ratio of Bcl-2/Bax. In addition, FPS-ZM1 improved hippocampal plasticity evidenced by enhanced in vivo LTP and the restoration of spine deficit and increased PSD-95 expression in hippocampal neuron. Further studies found that FPS-ZM1 treatment alleviated cognitive deficits shown by better performance in behavioral tests, without significant metabolic effects on blood glucose, insulin and cerebral AGEs. CONCLUSION: Downregulation of abnormal Aβ influx across the BBB by FPS-ZM1 at higher dosage contributes to reduced neuronal apoptosis, improved hippocampal plasticity and cognitive impairment in db/db mice.
Authors: Yuhuan Li; Huayuan Tang; Nicholas Andrikopoulos; Ibrahim Javed; Luca Cecchetto; Aparna Nandakumar; Aleksandr Kakinen; Thomas P Davis; Feng Ding; Pu Chun Ke Journal: Adv Nanobiomed Res Date: 2020-11-26
Authors: Elvis Cuevas; Hector Rosas-Hernandez; Susan M Burks; Manuel A Ramirez-Lee; Aida Guzman; Syed Z Imam; Syed F Ali; Sumit Sarkar Journal: Metab Brain Dis Date: 2019-07-02 Impact factor: 3.584