Authors: Kowthavarapu Venkata Krishna, Sunil Kumar Dubey, Ranendra Narayan Saha
Published: 2020-12-07
DOI: 10.1002/alz.043403
Source: Full article
AbstractBackgroundAlzheimer’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‐amyloid1‐42 induced cognitive deficits rats. To the best of our knowledge, this is the first report on self‐assembling nanomedicine of MEM.MethodMEM‐DHA was synthesized by amide coupling reaction and thoroughly characterized by 1H NMR, 13C 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 H2O2. Animals were injected with β‐amyloid1‐42 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.ResultThe formation of MEM‐DHA conjugate was confirmed by 1H NMR, 13C 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.ConclusionThe MEM‐DHA conjugate nanomedicine was successfully prepared, thoroughly characterized and has shown improved neuroprotective efficacy in cognitive induced rats.