Designing Novel Nanoformulations Targeting Glutamate Transporter Excitatory Amino Acid Transporter 2: Implications in Treating Drug Addiction - PubMed (original) (raw)

Designing Novel Nanoformulations Targeting Glutamate Transporter Excitatory Amino Acid Transporter 2: Implications in Treating Drug Addiction

Pss Rao et al. J Pers Nanomed. 2015.

Abstract

Chronic drug abuse is associated with elevated extracellular glutamate concentration in the brain reward regions. Deficit of glutamate clearance has been identified as a contributing factor that leads to enhanced glutamate concentration following extended drug abuse. Importantly, normalization of glutamate level through induction of glutamate transporter 1 (GLT1)/ excitatory amino acid transporter 2 (EAAT2) expression has been described in several in vivo studies. GLT1 upregulators including ceftriaxone, a beta-lactam antibiotic, have been effective in attenuating drug-seeking and drug-consumption behavior in rodent models. However, potential obstacles toward clinical translation of GLT1 (EAAT2) upregulators as treatment for drug addiction might include poor gastrointestinal absorption, serious peripheral adverse effects, and/or suboptimal CNS concentrations. Given the growing success of nanotechnology in targeting CNS ailments, nanoformulating known GLT1 (EAAT2) upregulators for selective uptake across the blood brain barrier presents an ideal therapeutic approach for treating drug addiction. In this review, we summarize the results obtained with promising GLT1 (EAAT2) inducing compounds in animal models recapitulating drug addiction. Additionally, the various nanoformulations that can be employed for selectively increasing the CNS bioavailability of GLT1 (EAAT2) upregulators are discussed. Finally, the applicability of GLT1 (EAAT2) induction via central delivery of drug-loaded nanoformulations is described.

Keywords: Drug addiction; EAAT2; Glutamate; Nanoparticles; Transcytosis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Figure 1

A schematic diagram of proposed mechanism of action for ceftriaxone-loaded nanoparticles. Antibody targeting the transferrin receptors will facilitate the selective uptake of ceftriaxone-loaded nanoparticles across the blood brain barrier. Upon entering the brain, the ceftriaxone released from these nanoparticles will induce the expression of GLT1 (EAAT2) in glial cell. Increased levels of glutamate transporters will facilitate the reuptake of glutamate and decrease the extracellular glutamate concentrations. The resumption of glutamate homeostasis will in principle result in attenuation of drug-seeking behavior.

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