Pharmacological, toxicological and neuronal localization assessment of galantamine/chitosan complex nanoparticles in rats: future potential contribution in Alzheimer’s disease management

Abstract

Purpose: Nasal galantamine hydrobromide (GH)/chitosan complex nanoparticles (CX-NP2) could have an improved therapeutic potential for managing Alzheimer's disease (AD). The current study aimed to investigate if the complexation reaction between GH and chitosan altered the pharmacological and toxicological profiles of the parent drug; GH. Methods: The nasal administration of CX-NP2 to male Wistar rats for 12 consecutive days was compared to negative control group, and oral and nasal GH solutions treated groups in 3 mg/kg daily GH dose. Brain acetylcholinesterase (AChE) protein level and activity were assessed. The in vivo toxicity of CX-NP2 was evaluated via monitoring the clinical signs throughout the study. Histopathological examination of brain sections was performed. The intracellular localization of CX-NP2 within brain neurons was investigated using transmission electron microscopy. Results: GH/chitosan complexation did not negatively alter the pharmacological efficiency of GH. Intriguingly, nasal CX-NP2 exhibited a significant decrease of AChE protein level and activity in rat brains compared to the oral and nasal GH solutions. No toxicity signs or histopathological manifestations were noticed. The nanoparticles were found intracellularly in the brain neurons. Conclusion:The pharmacological efficacy and in vivo safety of nasal CX-NP2 confirm their promising potential to contribute to the management of AD intranasally.

Biodegradable Nanoparticles for Delivery of Therapeutics in CNS Infection

“…The chitosan complexes were used to encapsulate galantamine, a drug used to manage mild to moderate Alzheimer’s disease. This study showed no toxicity or histopathological signs and decreased the level of AChE protein and activity in the brains of rats (Hanafy et al 2016). The efficacy and safety of these gelatin nanoparticles make them a promising candidate in future research of nasally delivered drugs.…”

“…These nanoparticles are of particular interest because they possess the capability to cross mucus membranes, specifically the nasal cavity and intestinal tract, as they are able open tight junctions of epithelial cells (Vila et al 2002, Grabowski et al 2015). Due to chitosan’s unique ability to cross mucus membranes, a 2016 study utilized the nasal administration of chitosan nanoparticles (Hanfy et al 2016). The chitosan complexes were used to encapsulate galantamine, a drug used to manage mild to moderate Alzheimer’s disease.…”

Use of Biodegradable, Chitosan-Based Nanoparticles in the Treatment of Alzheimer’s Disease

“…For example, it was confirmed that intranasal administration of galantamine NPs did not lead to histopathological manifestations in the olfactory-bulb, neither in other brain regions including the orbitofrontal cortex, parietal cortex or hippocampus. Furthermore, orbitofrontal cortex neurons also exhibited intact nuclear membrane, mitochondria as well as endoplasmic reticulum after the uptake of chitosan-GAL NPs [ 42 , 50 ]. Aside using biodegradable and biocompatible polymers to build nanocarriers of AD therapeutics, special attention has to be paid to synthetize the NPs without using toxic additives, surfactants or solvents.…”

“…With the intention of reducing side-effects of galantamine, Hanafy and coworkers encapsulated the API in chitosan NPs by inotropic gelation [ 42 , 50 ]. The chitosan-GAL nanoformula was administered to male Wistar rats intranasally (3 mg/kg/day).…”

Targeted Nanoparticles for the Treatment of Alzheimer's Disease

“…The cationic surface of chitosan nanoparticles is responsible for the mucoadhesive properties of the chitosan-based nanocarriers that facilitate the retention in the site of interest, thus providing a sustained release of the encapsulated drug. For this reason chitosan nanoparticles are considered very promising candidates for the Alzheimer treatments through intra-nasal administration [144,145].…”