A Novel Galantamine-Curcumin Hybrid as a Potential Multi-Target Agent against Neurodegenerative Disorders

Abstract

The acetylcholinesterase (AChE) inhibitors are the main drugs for symptomatic treatment of neurodegenerative disorders like Alzheimer’s disease. A recently designed, synthesized and tested hybrid compound between the AChE inhibitor galantamine (GAL) and the antioxidant polyphenol curcumin (CU) showed high AChE inhibition in vitro. Here, we describe tests for acute and short-term toxicity in mice as well as antioxidant tests on brain homogenates measured the levels of malondialdehide (MDA) and glutathione (GSH) and in vitro DPPH, ABTS, FRAP and LPO inhibition assays. Hematological and serum biochemical analyses were also performed. In the acute toxicity tests, the novel AChE inhibitor given orally in mice showed LD50 of 49 mg/kg. The short-term administration of 2.5 and 5 mg/kg did not show toxicity. In the ex vivo tests, the GAL-CU hybrid performed better than GAL and CU themselves; in a dose of 5 mg/kg, it demonstrates 25% reduction in AChE activity, as well as a 28% and 73% increase in the levels of MDA and GSH, respectively. No significant changes in blood biochemical data were observed. The antioxidant activity of 4b measured ex vivo was proven in the in vitro tests. In the ABTS assay, 4b showed radical scavenging activity 10 times higher than the positive control butylhydroxy toluol (BHT). The GAL-CU hybrid is a novel non-toxic AChE inhibitor with high antioxidant activity which makes it a prospective multitarget drug candidate for treatment of neurodegenerative disorders.

A Galantamine–Curcumin Hybrid Decreases the Cytotoxicity of Amyloid-Beta Peptide on SH-SY5Y Cells

“…The similar effects suggest a similar mode of action— 4b might act as an allosteric modulator of α7 nAChRs. Recently, we found that 4b is a low-toxic compound (LD 50 in mice was 49 mg/kg), inhibits AChE in vivo and in vitro better than GAL, and demonstrates high antioxidant activity in vitro and ex vivo outperforming the activities of both GAL and CU [ 21 ]. Together with the findings in the present study, 4b has emerged as a promising multi-target agent for a complex treatment of neurodegenerative disorders.…”

“…As GAL derivatives, compounds 4b and 8 were expected also to reduce the toxic effects of Aβ. As the present study was a continuation of our previous research [ 16 , 21 ], we preferred to keep the original compound IDs.…”

Chronic Stress and Oxidative Stress as Common Factors of the Pathogenesis of Depression and Alzheimer’s Disease: The Role of Antioxidants in Prevention and Treatment

“…It is a new IAChE, which is a combination of galantamine and curcumin. In ex vivo tests, the fusion of the two compounds is more effective than their separate administration [ 239 ]. This combination is based on the strong antioxidant properties of curcumin and the AChE inhibitory activity of galantamine [ 240 ].…”

Discovery of a Novel Acetylcholinesterase Inhibitor by Fragment-Based Design and Virtual Screening

“…Galantamine (GAL) is one of the most widely prescribed drugs for treating AD [13]. Apart from being an AChE inhibitor, GAL is an allosteric modulator of nicotinic ACh receptor [14], has antioxidant properties [15] and facilitates the clearance of Aβ peptide in rat brains [16]. Due to this variety of actions, GAL can serve as а multitarget scaffold to design new derivatives with a higher AChE inhibitory effect and lower toxicity.…”