Enhancement in the Neuroprotective Power of Riluzole Against Cerebral Ischemia Using a Brain Targeted Drug Delivery Vehicle

Abstract

Riluzole is the only available drug for motor neuron diseases quite well-known for its neuroprotective activity. But its poor aqueous solubility, short half-life with some side-effects at higher concentration poses a limitation to its use as a therapeutic agent. The present study was performed to investigate the therapeutic potential of nanoriluzole (NR), i.e., riluzole encapsulated in nanoparticles against cerebral ischemia (stroke) at three different concentrations [10 (NRL), 20 (NRM), and 40 (NRH) μg/kg body weight intraperitoneally (i.p.)]. Chitosan conjugated NIPAAM (N-isopropylacrylamide) nanoparticles coated with tween80 were synthesized through free radical polymerization. The particles were characterized with Transmission Electron Microscopy, Dynamic Light Scattering, and Fourier Transform Infrared spectroscopy and were found to have size of ∼50 nm. Cerebral ischemia was induced by Middle Cerebral Artery Occlusion (MCAO) model for 1 h and NR was given intraperitoneally after 1 h of MCAO. Animals were dissected after a reperfusion period of 24 h for evaluation of various parameters. Triphenyl tetrazolium chloride staining shows substantial reduction in infarct size in all three treated groups. It was also supported by histopathological results, biochemical parameters, and behavioral studies. Immunological parameters like NOS-2, NF-kB, and COX-2 also show profound reduction in expression in NR treated groups. Thus, the present work clearly demonstrated that the nanoparticle was good enough to carry large amount of drug across the Blood Brain Barrier which results in significant neuroprotection even at a very low concentration. It also substantially lowered the required concentration by overcoming the poor aqueous solubility; hence hardly leaving any scope for side-effects.

Functional identification of activity‐regulated, high‐affinity glutamine transport in hippocampal neurons inhibited by riluzole

“…; Verma et al . ). Riluzole is more effective as a neuroprotective agent when given prophylactically, which is in line with its presumed role to reduce synaptic Glu release and resultant Glu‐induced excitotoxicity post‐synaptically.…”

“…Riluzole has received renewed attention as an anti‐glutamatergic agent because of novel methods that increase its brain penetration (Verma et al . ), the reported beneficial effects of riluzole in animal models of Alzheimer's disease (Hunsberger et al . ; Mokhtari et al .…”

<p>Nanocarriers for Stroke Therapy: Advances and Obstacles in Translating Animal Studies</p>

“…[62][63][64][65][66][67][68] An alternative strategy involves ligands to bind receptors and alter intracellular signalling, such as the channel blockers, MRZ2/576 and riluzole, as well as the neuropeptide, nerve growth factor (NGF). [69][70][71] Another unique strategy is to deliver nucleic acids to modulate gene expression instead, such as miR-195, C3 siRNA and other plasmid vectors. [72][73][74] Free radicals had also been used as ROS scavengers among different treatment approaches to reduce I/R injury.…”

Cell and Tissue Instructive Materials for Central Nervous System Repair

“…[158] Typical approaches involve the use of functionalized NPs to cross the BBB engulfing neurotrophic or neuroprotective molecules. [152,[159][160][161] Using these concepts, Gaudin et al developed squalenoyl NPs encapsulating adenosine and showed that these lipid particles were able to enhance the neuroprotective effect of this molecule. These were mainly attained by protecting the precocious metabolization of adenosine in the bloodstream and maximizing its interaction with the neurovascular unit.…”