Is it All Said for NSAIDs in Alzheimer’s Disease? Role of Mitochondrial Calcium Uptake

Abstract

Objectives: Epidemiological data suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD). Unfortunately, recent trials have failed in providing compelling evidence of neuroprotection. Discussion as to why NSAIDs effectivity is uncertain is ongoing. Possible explanations include the view that NSAIDs and other possible disease-modifying drugs should be provided before the patients develop symptoms of AD or cognitive decline. In addition, NSAID targets for neuroprotection are unclear. Both COX-dependent and independent mechanisms have been proposed, including γ-secretase that cleaves the amyloid precursor protein (APP) and yields amyloid β peptide (Aβ). Methods: We have proposed a neuroprotection mechanism for NSAIDs based on inhibition of mitochondrial Ca2+ overload. Aβ oligomers promote Ca2+ influx and mitochondrial Ca2+ overload leading to neuron cell death. Several non-specific NSAIDs including ibuprofen, sulindac, indomethacin and Rflurbiprofen depolarize mitochondria in the low µM range and prevent mitochondrial Ca2+ overload induced by Aβ oligomers and/or N-methyl-D-aspartate (NMDA). However, at larger concentrations, NSAIDs may collapse mitochondrial potential (ΔΨ) leading to cell death. Results: Accordingly, this mechanism may explain neuroprotection at low concentrations and damage at larger doses, thus providing clues on the failure of promising trials. Perhaps lower NSAID concentrations and/or alternative compounds with larger dynamic ranges should be considered for future trials to provide definitive evidence of neuroprotection against AD.

Mitochondrial Calcium Deregulation in the Mechanism of Beta-Amyloid and Tau Pathology

“…Other authors have proposed that the induction of a mild mitochondrial uncoupling with different agents such as non-steroidal anti-inflammatory drugs (NSAIDs) could also reduce mitochondrial Ca 2+ uptake and prevent overload induced by β-amyloid, protecting neurons against cell death in AD [ 124 ]. Results from trials have been however conflicting, probably due to the narrow effective dose window for this strategy, as high doses might lead to opposite effects and collapse the ΔΨm [ 125 ].…”

Neurovascular unit dysregulation, white matter disease, and executive dysfunction: the shared triad of vascular cognitive impairment and Alzheimer disease

“…Aβ activates several TNF-αdependent pathways, including cyclooxygenase (COX)-mediated inflammatory processes (Medeiros et al 2010). Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce these inflammatory processes by inhibiting COX in neurons, microglia, and astrocytes (Krause and Müller 2010;Zhang et al 2018), and NSAIDs may also offer neuroprotection by COXindependent pathways such as the direct promotion of nonamyloidogenic processing of amyloid precursor protein (Kukar and Golde 2008;Zhang et al 2018;Sanz-Blasco et al 2018). Cohort studies have shown promise in reducing the risk of AD, with the most recent metaanalysis of 236,000 participants from 16 cohort studies citing a 19% relative risk reduction of AD diagnosis (Zhang et al 2018).…”

Quality by Design Based Formulation Study of Meloxicam-Loaded Polymeric Micelles for Intranasal Administration

“…Subsequently, numerous studies have demonstrated their pharmacological activity in the central nervous system (CNS). Treating neuroinflammation by NSAIDs could be possibly based on protection by depolarizing the mitochondria and inhibiting the calcium uptake, due to the ionizable carboxylic group, having a similar effect to mild mitochondrial uncouplers [5,6]. However, the blood-brain barrier (BBB) is an obstacle to the therapy because it prevents the release of active substances that could be used by its protective function [7].…”