Lactoferrin Coupled Lower Generation PAMAM Dendrimers for Brain Targeted Delivery of Memantine in Aluminum-Chloride-Induced Alzheimer’s Disease in Mice

Abstract

Lower generation PAMAM dendrimers have an immense potential for drug delivery with lower toxicity, but these dendrimers yet need certain basic ameliorations. In this study, the brain delivery potential of the synthesized PAMAM-Lf (lower generation PAMAM and lactoferrin conjugate) loaded with memantine (MEM) was explored and evaluated in vitro and in vivo in the disease-induced mouse model. The developed nanoscaffolds were characterized for size, zeta potential and in vitro release. Increase in the average size from 11.54 ± 0.91 to 131.72 ± 4.73 nm, respectively, was observed for drug-loaded PAMAM (i.e., PAMAM-MEM) and PAMAM-Lf (i.e., MEM-PAMAM-Lf). Release profile of MEM from MEM-PAMAM-Lf was slow and sustained up to 48 h. In vivo biodistribution in the Sprague−Dawley rat model revealed that the brain uptake of MEM-PAMAM-Lf was significantly higher than that of MEM alone. The behavioral response study in the healthy rats did not result in any significant changes. The in vivo study in an AlCl 3 -induced Alzheimer's (AD) mice model showed a significant improvement in behavioral responses. Optical density, which reflects the acetylcholinesterase (AChE) activity, was highest in the AL group 0.16 ± 0.01 (higher than the CON group, 0.09 ± 0.02; p < 0.05). No significant suppression of AChE activity was recorded in all the other treated groups. Similarly, the DOPAmine and 3,4 dihydroxyphenylacetic acid (DOPAC) levels were unaffected by the developed formulations. The study reported improved brain bioavailability of MEM in AlCl 3 -induced Alzheimer's mice leading to improved memory, with the resultant mechanism behind in a descriptive manner. This study is among the preliminary studies reporting the memory improvement aspect of PAMAM-Lf conjugates for MEM in AlCl 3 -AD induced mice. The formulation developed was beneficial in AD-induced mice and had a significant impact on the memory aspects.

Curcumin Attenuated Neurotoxicity in Sporadic Animal Model of Alzheimer’s Disease

“…Indeed, a strong decrease in choline acetyltransferase activity in the cortex and hippocampus has been related to human memory and cognitive dysfunction in AD patients [ 26 ]. Our data showed that AChE activity decreased in hippocampus of AlCl 3 -exposed rats, which corroborate with recent studies suggesting that the administration of AlCl 3 decreases acetylcholinesterase activity in mouse [ 23 ] and rat brains [ 25 ]. Recently, Martinez et al showed that the dose of 100 mg/kg of AlCl 3 inhibits AChE activity on the hippocampus of rat after 60 days of treatment, confirming the inhibition of cholinergic activity [ 27 ].…”

“…In addition, this model is increasingly used to study bioactive/chemical molecules potential on the treatment of this pathology and to follow up drug intervention studies. In fact, data on AlCl 3 exposed mice are consistent with the main pathological features (oxidative stress, inflammation and apoptosis) of clinical AD [ 23 , 24 ], indicating that the sporadic AD rat model used in this work meets the experimental AD study requirements. Thus, in the present study, we focused on the therapeutic and recovery effects of CUR on chronic AlCl 3 -exposed rats.…”

Nanomedicine: A Promising Way to Manage Alzheimer’s Disease

“…A novel finding has been achieved by coupling the lactoferrin and low-generation dendrimers for brain-targeted delivery of memantine in ADinduced mice. A recent study has reported the significant impact on the memory aspects in target mice (Gothwal et al, 2019).…”

Nano Carrier Drug Delivery Systems for the Treatment of Neuropsychiatric Disorders: Advantages and Limitations

“…Despite the best results in improving cognitive impairments in patients, the clinical applicability of MEM is limited. MEM should be administered daily, which leads to poor compliance with the drug regimen [205]. The development of nanocarriers with memantine can help to solve these problems.…”

“…The profile of memantine release from nanoparticles was slow and persisted for up to 48 h. The brain absorption of NPs was significantly higher than that of pure memantine. The in vivo research in an AlCl3-induced AD mice model demonstrated a considerable improving in behavioral tests [205].…”