Can an FDA-Approved Alzheimer's Drug Be Repurposed for Alleviating Neuronal Symptoms of Zika Virus?

Abstract

Zika virus caught the world by surprise by its rapid spread and frightening disease outcomes. This major epidemic motivated many scientists to focus their attention on controlling this emerging pathogen. As many as 45 vaccine candidates are being developed, but progress in the antiviral arena has been slower. In a recent article (mBio 8:e00350-17, 2017, https://doi.org/10.1128/mBio.00350-17), Costa and colleagues showed that an FDA-approved drug used to treat Alzheimer's disease may moderate Zika virus-induced neuronal damage. This work is based on the premise that overstimulation of N-methyl-d-aspartate receptors (NMDARs) may drive neurodegeneration and that this may be responsible for neuronal cell death associated with Zika virus infection of the central nervous system (CNS). Thus, blockage of the NMDAR channel activity with FDA-approved memantine or other antagonists may reduce neurological complications associated with Zika virus infection. Repurposing a preapproved drug and targeting the host represent intriguing strategies and yet require more analysis prior to moving into clinical trials.

Keywords: NMDAR; Zika virus; antiviral agents; memantine; neurodegeneration.

FIG 1

Glutamate neurotransmission, homeostasis, and excitotoxicity in the brain. (A) A glutamate-driven chemical synapse along with a neighboring astrocyte and an activated microglia are shown. Under physiological conditions, a depolarizing impulse on the presynaptic neuron triggers a transient spike in the concentration of glutamate in the synaptic cleft. Glutamate binds to NMDA and AMPA ionotropic glutamate receptor families on the postsynaptic neuron. These receptor channels, when activated, allow the flow of Na⁺-K⁺, leading to an excitatory postsynaptic potential. If the threshold is achieved, an action potential is generated at the axon hillock of the postsynaptic neuron. NMDAR, in addition to Na⁺-K⁺, also allows conductivity of Ca²⁺ ions. Ca²⁺ ions trigger a signaling cascade that helps modulate the strength of the synapse (a magnified view of the inset is provided in panel B). Under neurodegenerative pathological conditions such as those associated with Alzheimer’s disease or, potentially, Zika virus infection, NMDAR may be hyperactivated, leading to Ca²⁺ overload in cells and subsequent death of the postsynaptic neuron through a process termed "glutamate excitotoxicity." Glutamate levels are tightly regulated in the brain. Glutamate does not cross the adult blood-brain barrier and is synthesized in the brain de novo from an intermediate of the TCA cycle. It is efficiently and swiftly cleared from the synapses by EAATs, especially EAAT2 (localized on astrocytes). Glutamate is shuttled between astrocytes and neurons by the glutamate-glutamine cycle and is packaged into synaptic vesicles in neurons by vGLUT. Glutamate homeostasis may be perturbed under pathological conditions or during infection by Zika virus by a variety of mechanisms such as (i) oxidative stress, mitochondrial dysfunction, or energy deficiency (via loss of ATP-dependent Na⁺/K⁺ pumps), which can cause chronic or excessive release of glutamate from the presynaptic neurons; (ii) the release of large amounts of glutamate from activated microglia mediated by Xc⁻ antiporters; and (iii) the reduction of glutamate clearance from synaptic clefts due to compromised activity of EAATs on astrocytes. This could occur due to the presence of ROS and inflammatory cytokines produced by activated microglia or due to damage (or possibly due to infection) in astrocytes themselves. The net result is the unprovoked and sustained presence of glutamate in the synaptic cleft and chronic activation of NMDAR, leading to neuronal damage. NMDAR may also be hyperactivated if the ambient glycine levels in the synaptic cleft are perturbed due to malfunctioning of the glycine transporters (GlyT1). NMDAR antagonists such as FDA-approved memantine, MK-801, agmatine, and ifenprodil (specific for NMDAR containing GluN2B subunits) were shown to prevent neuronal damage during Zika virus infection, but the mechanism leading to hyperactivation of NMDAR during Zika virus infection remains unknown. (B) Activation and functioning of ionotropic glutamate receptors NMDAR and AMPAR. Both NMDAR and AMPAR represent ligand gated ion channels that often coexist at synapses and allow flow of cations in accordance with their concentration gradients. The font size of the ions shown is proportional to their relative concentrations to predict the direction of flow of ions across the membrane. NMDAR allows passage of Na⁺, K⁺, and Ca²⁺ ions, while the prevalent GluA2 subunit containing AMPAR is conductive for Na⁺-K⁺ only. NMDAR requires glutamate and glycine for activation, while glutamate is the exclusive ligand for AMPAR. During a normal or weak synaptic event, only the fast AMPAR channels are activated whereas the slow NMDARs, though bound by ligands, remain inactive due to the obstruction imposed by the nonpermeant Mg²⁺ ion. NMDARs are coincidence detectors and require both ligand and voltage for activation. A depolarization of adequate amplitude/duration by neighboring AMPAR channels results in the repulsion of Mg²⁺ ion from the NMDAR channels, which are then opened, allowing the flow of cations, including Ca²⁺. Influx of Ca²⁺ in cells activates a signaling cascade that regulates synaptic strength and plasticity. Abbreviations: NMDA, N-methyl-d-aspartate receptor; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; EAAT, excitatory amino acid transporter; vGLUT, vesicular glutamate transporter; Xc⁻, cystine-glutamate antiporter; GlyT1, glycine transporter; TCA, tricarboxylic acid (cycle); ROS, reactive oxygen species; OONO⁻, peroxynitrite; TNF-α, tumor necrosis factor alpha; IL-1β, interleukin-1β; A⁻, anion; H⁺, hydrogen; Ca²⁺, calcium; Mg²⁺, magnesium; Na⁺, sodium; K⁺, potassium.