Combining two repurposed drugs as a promising approach for Alzheimer's disease therapy

Abstract

Alzheimer disease (AD) represents a major medical problem where mono-therapeutic interventions demonstrated only a limited efficacy so far. We explored the possibility of developing a combinational therapy that might prevent the degradation of neuronal and endothelial structures in this disease. We argued that the distorted balance between excitatory (glutamate) and inhibitory (GABA/glycine) systems constitutes a therapeutic target for such intervention. We found that a combination of two approved drugs – acamprosate and baclofen – synergistically protected neurons and endothelial structures in vitro against amyloid-beta (Aβ) oligomers. The neuroprotective effects of these drugs were mediated by modulation of targets in GABA/glycinergic and glutamatergic pathways. In vivo, the combination alleviated cognitive deficits in the acute Aβ25–35 peptide injection model and in the mouse mutant APP transgenic model. Several patterns altered in AD were also synergistically normalised. Our results open up the possibility for a promising therapeutic approach for AD by combining repurposed drugs.

The GABAergic system as a therapeutic target for Alzheimer's disease

“…When tested in vivo, PXT‐864 was able to substantially and significantly restore Aβ‐induced impairments in a range of hippocampal‐dependent learning and memory paradigms (Chumakov et al . ). As shown in this study, combined drug therapy for AD has some benefits over mono‐therapeutics, as it takes into account the multifactorial nature of the disorder.…”

“…GABA B receptor agonists As there are many different factors which contribute to AD pathogenesis and the complexity of the disease, it was proposed that a combinatorial drug approach might prove beneficial (Chumakov et al 2015). Chumakov and colleagues proposed targeting the E/I imbalance in AD by combining the effect of the GABA B R agonist baclofen with acamprosate, an inhibitor of glutamatergic neurotransmission (Chumakov et al 2015).…”

“…GABA B receptor agonists As there are many different factors which contribute to AD pathogenesis and the complexity of the disease, it was proposed that a combinatorial drug approach might prove beneficial (Chumakov et al 2015). Chumakov and colleagues proposed targeting the E/I imbalance in AD by combining the effect of the GABA B R agonist baclofen with acamprosate, an inhibitor of glutamatergic neurotransmission (Chumakov et al 2015). The combined drug, named PXT-864, protected neurons and endothelial structures, even at low doses, from Ab oligomer-induced damage in vitro, including apoptosis, oxidative stress, inflammation, and tau hyperphosphorylation (Chumakov et al 2015).…”

“…Chumakov and colleagues proposed targeting the E/I imbalance in AD by combining the effect of the GABA B R agonist baclofen with acamprosate, an inhibitor of glutamatergic neurotransmission (Chumakov et al 2015). The combined drug, named PXT-864, protected neurons and endothelial structures, even at low doses, from Ab oligomer-induced damage in vitro, including apoptosis, oxidative stress, inflammation, and tau hyperphosphorylation (Chumakov et al 2015). When tested in vivo, PXT-864 was able to substantially and significantly restore Ab-induced impairments in a range of hippocampaldependent learning and memory paradigms (Chumakov et al 2015).…”

Activation of the γ-Aminobutyric Acid Type B (GABAB) Receptor by Agonists and Positive Allosteric Modulators

“…2 Though they are ionotropic receptors, they have a distinct pharmacology from GABA A receptors, being resistant to both the GABA A antagonist bicuculline and the sedative/hypnotic drugs that target the GABA A 4 addition, the combination of baclofen and acamprosate was recently shown to be neuroprotective in a rodent model of Alzheimer's disease. 23 Despite its FDA approval for the treatment of muscle spasticity and a growing number of off-label and potential uses, baclofen is far from an ideal drug molecule. Baclofen has low penetration into the brain, 24 a property which may be ascribed to transport out of the brain via the organic acid transporter.…”