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Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and is associated with disrupted cognition and behavior. Neuroinflammatory pathogenesis is the main component that contributes to AD initiation and progression through microglial activation and neuronal damage. Thus, targeting inflammatory pathways may help manage AD. In this study, for the first time, the potential prophylactic and therapeutic effects of leflunomide were investigated either alone or in combination with rivastigmine in aluminum chloride (AlCl 3 )-induced AD-like rats using behavioral, biochemical, and histological approaches. Thirty-six adult male albino rats were divided into two protocols: the treatment protocol, subdivided into five groups (n = 6)-(1) control group, (2) AlCl 3 (50, 70, 100 mg/kg/I.P) group, (3) reference group (rivastigmine 2 mg/kg/P.O.), (4) experimental group (leflunomide 10 mg/kg/P.O.), and (5) combination group (rivastigmine + leflunomide); and the prophylactic protocol (leflunomide 10 mg/kg/P.O.), which started 2 weeks before AlCl 3 induction. The results showed that AlCl 3 disrupted learning and memory parameters in rats and increased amyloid-β plaque deposition and neurofibrillary tangle aggregation. Moreover, AlCl 3 administration markedly elevated acetylcholinesterase activity, nuclear factor-kappa β, tumor necrosis factor-α, and interleukin-1 beta, and marked degenerative changes in the pyramidal neurons. However, administration of leflunomide alone or with rivastigmine in AlCl 3 -induced AD rats restored most of the behavioral, biochemical, and histological parameters triggered by AlCl 3 in rats. Our findings suggest that leflunomide can potentially restore most of the neuronal damage in the hippocampal tissues of AlCl 3 -induced AD rats. However, these preclinical findings still need to be confirmed in clinical trials., (© 2022. The Author(s).)

With the increasing aging population and progressive nature of the disease, Alzheimer's disease (AD) poses to be an oncoming epidemic with limited therapeutic strategies. It is characterized by memory loss, behavioral instability, impaired cognitive function, predominantly, cognitive inability manifested due to the accumulation of β-amyloid, with malfunctioned cholinergic system. Rivastigmine, a reversible dual cholinesterase inhibitor, is a more tolerable and widely used choice of drug for AD. However, rivastigmine being hydrophilic and undergoing the first-pass metabolism exhibits low CNS bioavailability. Nanoformulations including liposomes and PLGA nanoparticles can encapsulate hydrophilic drugs and deliver them efficiently to the brain. Besides, the nasal route is receiving considerable attention recently, due to its direct access to the brain. Therefore, the present study attempts to evaluate the pharmacokinetic and pharmacodynamic properties of nasal liposomal and PLGA nanoparticle formulations of rivastigmine in acute scopolamine-induced amnesia and chronic colchicine induced cognitive dysfunction animal models, and validate the best formulation by employing pharmacokinetic and pharmacodynamic (PK-PD) modeling. Nasal liposomal rivastigmine formulation showed the best pharmacokinetic features with rapid onset of action (Tmax = 5 min), higher Cmax (1489.5 ± 620.71), enhanced systemic bioavailability (F = 118.65 ± 23.54; AUC = 35,921.75 ± 9559.46), increased half-life (30.92 ± 8.38 min), and reduced clearance rate (Kel (1/min) = 0.0224 ± 0.006) compared to oral rivastigmine (Tmax = 15 min; Cmax = 56.29 ± 27.05; F = 4.39 ± 1.82; AUC = 1663.79 ± 813.54; t1/2 = 13.48 ± 5.79; Kel (1/min) = 0.0514 ± 0.023). Further, the liposomal formulation significantly rescued the memory deficit induced by scopolamine as well as colchicine superior to other formulations as assessed in Morris water maze and passive avoidance tasks. PK-PD modeling demonstrated a strong correlation between the pharmacokinetic parameters and acetylcholinesterase inhibition of liposomal formulation., (© 2021. The Author(s).)

Central cholinergic dysfunction contributes to acute spatial memory deficits produced by ethanol administration. Donepezil and rivastigmine elevate acetylcholine levels in the synaptic cleft through the inhibition of cholinesterases-enzymes involved in acetylcholine degradation. The aim of our study was to reveal whether donepezil (acetylcholinesterase inhibitor) and rivastigmine (also butyrylcholinesterase inhibitor) attenuate spatial memory impairment as induced by acute ethanol administration in the Barnes maze task (primary latency and number of errors in finding the escape box) in rats. Additionally, we compared the influence of these drugs on ethanol-disturbed memory. In the first experiment, the dose of ethanol (1.75 g/kg, i.p.) was selected that impaired spatial memory, but did not induce motor impairment. Next, we studied the influence of donepezil (1 and 3 mg/kg, i.p.), as well as rivastigmine (0.5 and 1 mg/kg, i.p.), given either before the probe trial or the reversal learning on ethanol-induced memory impairment. Our study demonstrated that these drugs, when given before the probe trial, were equally effective in attenuating ethanol-induced impairment in both test situations, whereas rivastigmine, at both doses (0.5 and 1 mg/kg, i.p.), and donepezil only at a higher dose (3 mg/kg, i.p.) given prior the reversal learning, attenuated the ethanol-induced impairment in cognitive flexibility. Thus, rivastigmine appears to exert more beneficial effect than donepezil in reversing ethanol-induced cognitive impairments-probably due to its wider spectrum of activity. In conclusion, the ethanol-induced spatial memory impairment may be attenuated by pharmacological manipulation of central cholinergic neurotransmission., Competing Interests: Compliance with ethical standards All experimental protocols and housing conditions were approved by the Local Ethics Committee and carried out according to the National Institute of Health Guidelines for the Care and Use of Laboratory Animals and the European Community Council Directive of November 2010 for Care and Use of Laboratory Animals (Directive 2010/63/EU) and were approved by the Local Ethics Committee.