Design, synthesis and neuroprotective potency of self‐assembling memantine‐docosahexaenoic acid conjugate nanomedicine for the effective treatment of Alzheimer’s disease Nonhuman/Target identification and validation studies: Cognitive enhancement and other behavioral symptoms

• Published in: Alzheimer's & dementia Vol. 16; no. S9
• Main Authors: Krishna, Kowthavarapu Venkata, Dubey, Sunil Kumar, Saha, Ranendra Narayan
• Format: Journal Article
• Language: English
• Published: 01.12.2020
• DOI: 10.1002/alz.043403
• ISSN: 1552-5260

Abstract Background Alzheimer’s Disease (AD) is the most common type of dementia characterized with progressive neurodegeneration and seems to be irreversible, progressive and presently untreatable. Memantine (MEM), a N‐methyl‐D‐aspartate receptor antagonist has been approved by FDA for symptomatic relief in neurodegenerative disorders. Docosahexaenoic acid (DHA) is a brain essential omega‐3 fatty acid that has a vital role in functional development and growth of the brain in infants. It has been reported that the presence of DHA in the diet helps in cognitive enhancement. Hypothesizing the co‐delivery of MEM and DHA for the effective treatment of AD, herein our aim was to design and develop a novel self‐assembling MEM‐DHA conjugate nanomedicine and to investigate its neuroprotective potency on SH‐SY5Y cells. Furthermore, the efficacy of these nanoparticles was assessed in intracerebroventricular‐β‐amyloid 1‐42 induced cognitive deficits rats. To the best of our knowledge, this is the first report on self‐assembling nanomedicine of MEM. Method MEM‐DHA was synthesized by amide coupling reaction and thoroughly characterized by 1 H NMR, 13 C NMR and HR‐MS. The synthesized conjugate was self‐assembled into nanoparticles by using nanoprecipitation method and morphological characterization was performed by using dynamic light scattering technique and by FE‐SEM analysis. The neuroprotective activity was performed on human neuroblastoma SH‐SY5Y cells against oxidative stress induced by H 2 O 2 . Animals were injected with β‐amyloid 1‐42 through intracerebroventricular route and dosage administered for a period of 28 days in separate groups viz control, disease control, MEM, MEM‐DHA conjugate and MEM‐DHA nanoparticles. Learning, behavior, memory assessment and biochemical parameters were estimated. Result The formation of MEM‐DHA conjugate was confirmed by 1 H NMR, 13 C NMR and HR‐MS. MEM‐DHA conjugate has a property to self‐assemble into nanoparticles due to its amphiphilic nature. The average hydrodynamic size of the self‐assembled nanoparticles was found to be 144.30 ± 3.91 nm with a polydispersity index 0.181 ± 0.02 and zeta potential was ‐6.82 ± 0.51 (Fig.1.). Cell culture and animal studies revealed MEM‐DHA conjugate nanoparticles are having strong potential as a therapeutic delivery to restore memory impairment in AD. Conclusion The MEM‐DHA conjugate nanomedicine was successfully prepared, thoroughly characterized and has shown improved neuroprotective efficacy in cognitive induced rats.