Cellular and molecular characterization of multiple neuroprotections by Bis(propyl)-cognitin, a promising anti-Alzheimer's dimer

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Cellular and molecular characterization of multiple neuroprotections by Bis(propyl)-cognitin, a promising anti-Alzheimer's dimer

 

Author: Hu, Shengquan
Title: Cellular and molecular characterization of multiple neuroprotections by Bis(propyl)-cognitin, a promising anti-Alzheimer's dimer
Degree: Ph.D.
Year: 2014
Subject: Nervous system -- Degeneration.
Alzheimer's disease.
Hong Kong Polytechnic University -- Dissertations
Department: Dept. of Applied Biology and Chemical Technology
Pages: xvii, 122 leaves : ill. (some col.) ; 30 cm.
Language: English
InnoPac Record: http://library.polyu.edu.hk/record=b2681836
URI: http://theses.lib.polyu.edu.hk/handle/200/7391
Abstract: Neurodegenerative diseases such as Alzheimer's have emerged as a global issue, resulting in cognitive and behavioral problems, disability and economic burdens. Though their exact pathology remains unknown, neurodegenerative diseases are caused by, at least, inappropriate apoptosis as well as impairments in neurogenesis and neuronal differentiation. Compounds with anti-apoptotic property and neuronal differentiation-promoting activities could potentially have therapeutic significance against these devastating disorders. Bis(propyl)-cognitin (B3C), a novel dimer derived from tacrine, has been shown as a multifunctional agent effectively against the key processes in neurodegenerative diseases on the basis of AChE inhibition and uncompetitive NMDA receptor antagonism. Moreover, B3C has been demonstrated to exert neuroprotections in middle cerebral artery occlusion-induced brain damage in vivo. However, the detailed molecular mechanisms of neuroprotection remain to be further elucidated. In this research, the multiple neuroprotections and underlying mechanisms by which B3C protects against glutamate or potassium (K+) deprivation-induced apoptosis in primary cultured cerebellar granule neurons (CGNs) were examined. In addition, the neuronal differentiation-promoting activity of B3C was also investigated using PC12 cells and primary cultured cortical neurons. In primary cultures of CGN, B3C (IC50, 0.45 μM) substantially prevents glutamate-induced apoptosis with a potency approximately 10 times stronger than memantine (IC50, 4.58 μM), an effective anti-Alzheimer’s drug approved by the FDA on the basis of NMDA receptor blockade. The neuroprotection of B3C is found to be associated with the blockade of NMDA receptors and subsequent regulation of NO, ERK and PI3-K/Akt/GSK3β pathways. In addition, B3C remarkably protects against K+ deprivation-induced apoptosis in CGNs independent of its AChE inhibition and NMDA receptor antagonism, but through reversing the inhibition of vascular endothelial growth factor receptor-2 (VEGFR-2) /Akt/ GSK3β and VEGFR-2/ERK signaling pathways. Furthermore, B3C effectively induced neurite outgrowth in PC12 cells and primary cultured cortical neurons in a concentration-and time-dependent manner, as evidenced by the up-regulation of two neuron-specific protein markers growth-associated protein-43 and βIII-tubulin, and the neurite outgrowth-promoting activity of B3C correlates with the activation of α7-type nicotinic acetylcholine receptor (α7-nAChR). In conclusion, B3C provides powerful neuroprotections by blocking NMDA receptor or activating VEGFR-2, and subsequently regulating pro-survival downstream signaling pathways. Moreover, B3C promotes neuronal differentiation by activating α7-nAChR. All these results, taken together, offer not only novel molecular insights into the therapeutic potential of B3C, but also a new experimental approach for developing new agents to modify or slow down the disease progression of Alzheimer’s and other related neurodegenerative disorders.

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