Age-Related Decline in Brain and Hepatic Clearance of Amyloid-Beta is Rectified by the Cholinesterase Inhibitors Donepezil and Rivastigmine in Rats

Abstract

In Alzheimer’s disease (AD), accumulation of brain amyloid-β (Aβ) depends on imbalance between production and clearance of Aβ. Several pathways for Aβ clearance have been reported including transport across the blood-brain barrier (BBB) and hepatic clearance. The incidence of AD increases with age and failure of Aβ clearance correlates with AD. The cholinesterase inhibitors (ChEIs) donepezil and rivastigmine are used to ease the symptoms of dementia associated with AD. Besides, both drugs have been reported to provide neuroprotective and disease-modifying effects. Here, we investigated the effect of ChEIs on age-related reduced Aβ clearance. Findings from in vitro and in vivo studies demonstrated donepezil and rivastigmine to enhance 125I-Aβ40 clearance. Also, the increase in brain and hepatic clearance of 125I-Aβ40 was more pronounced in aged compared to young rats, and was associated with significant reduction in brain Aβ endogenous levels determined by ELISA. Furthermore, the enhanced clearance was concomitant with up-regulation in the expression of Aβ major transport proteins P-glycoprotein and LRP1. Collectively, our findings that donepezil and rivastigmine enhance Aβ clearance across the BBB and liver are novel and introduce an additional mechanism by which both drugs could affect AD pathology. Thus, optimizing their clinical use could help future drug development by providing new drug targets and possible mechanisms involved in AD pathology.

Role of P-glycoprotein in mediating rivastigmine effect on amyloid-β brain load and related pathology in Alzheimer's disease mouse model

“…Following to our previous findings [13], this study aims to investigate the question “how changes in P-gp expression would affect rivastigmine therapeutic effect, including Aβ lowering effect, neuroprotection and anti-inflammatory effect using APPSW mice that carry APP transgene and P-gp WT (APP/mdr1 +/+ ), P-gp one copy (APP/mdr1 +/− ), or P-gp knockout (APP/mdr1 −/− ) mice. Overall findings suggest that P-gp mediates the non-cholinergic effects of rivastigmine, and that understanding various mechanisms of action of rivastigmine is important to optimize its clinical utility for AD patients.…”

“…Rivastigmine is a dual cholinesterase inhibitor which acts by inhibiting degradation of ACh at synapses and improving cholinergic transmission that is known to be impaired in AD. Recently, we have shown that FDA-approved drugs for AD modulate Aβ transport by up-regulating the expression of P-gp and LRP1 at the BBB and hepatocytes [13]. Among those drugs, we found that rivastigmine was most efficient to induce the expression of P-gp and LRP1 in the brains of aged rats and were associated with reduced levels of endogenous Aβ 40 and Aβ 42 [13].…”

“…In one study, rivastigmine has shown to induce presynaptic proteins, preserve neuronal viability and regulate APP processing and Aβ production in vitro [10–12]. Recently, we have demonstrated a novel mechanism for rivastigmine to reduce Aβ brain load by enhancing its clearance through induction of Aβ major transport proteins, low-density lipoprotein receptor related protein-1 (LRP1) and P-glycoprotein (P-gp), at the BBB and liver [13]. These findings suggest that rivastigmine therapeutic effect is exerted through multiple mechanisms that interfere with Aβ pathogenesis and not limited to cholinesterase inhibition.…”

Assessment of Enzyme Inhibition: A Review with Examples from the Development of Monoamine Oxidase and Cholinesterase Inhibitory Drugs<strong> </strong>

“…It is a reversible AChE inhibitor that binds to the peripheral anionic site, and does not affect BChE. It has symptomatic effects in AD treatment but, like rivastigmine, it also appears to delay the deposition of amyloid plaque (see [94]) or to enhance plaque removal [121]. It has a relatively long half-life in vivo (about 70 h), reducing the need for too frequent dosage.…”

Toluidine blue O is a potent inhibitor of human cholinesterases

“…In addition to these pathologies, the decline in level of neurotransmitter acetylcholine (ACh) and cholinergic dysfunction are also observed in AD [4e6]. Most of AD drugs, currently available on the market, which are approved by FDA, have been developed to increase ACh levels and to improve the cognitive function by inhibiting acetylcholinesterase (AChE, EC 3.1.1.7) [7]. However, these treatments become ineffective as disease progresses since they do not prevent the synaptic loss.…”