Nose to brain delivery of melatonin lipidic nanocapsules as a promising post-ischemic neuroprotective therapeutic modality

Abstract

Ischemic stroke accounts for about 87% of all strokes, causing long-term disability in adults, and is the second leading cause of death worldwide. In search of new therapeutic modalities, the use of neuroprotective agents loaded in nanocarriers to be delivered by noninvasive means (i.e. via intranasal route) became a popular approach. In the current study, melatonin (MEL) was loaded in lipidic nanocapsules (LNCs) prepared using the phase inversion method, and characterized in terms of size, polydispersity, zeta potential, in vitro drug release, viscosity, storage stability, and ex vivo permeation across sheep nasal mucosa. Moreover, MEL-LNCs were tested for efficacy in cerebral ischemia/reperfusion (I/R/) injury model through histopathological assessment, and analysis of oxidative stress markers, pro-inflammatory cytokines, and apoptotic markers. Results showed that LNCs exhibited particle size ranging from 18.26 to 109.8 nm, negative zeta potential, good storage stability, spherical morphology, and a burst release followed by a sustained release pattern. LNCs exhibited 10.35 folds higher permeation of MEL than the drug solution across sheep nasal mucosa. Post-ischemic intranasal administration of MEL-LNCs revealed lowering of oxidative stress manifested by a decrease in malondialdehyde levels, and elevation of glutathione and superoxide dismutase levels, lowering of the inflammatory markers tumor necrosis factor-α, NO, myeloperoxidase, and significant inhibition of Caspase-3 activity as an apoptotic marker. Western blot analysis delineated a recovery of protein expression Nrf-2 and HO-1 with downregulation in the parent inflammatory markers nuclear factor kappa B p65, inducible nitric oxide synthase, Bax, and Cytochrome C expressions, and upregulation of B-cell lymphoma-2 Bcl-2, hence promoting neuronal survival. This was supported by histological evidence, revealing significant restoration of hippocampal neurons. In light of the above, it can be concluded that MEL-LNCs could be a promising delivery system for nose to brain delivery for treatment of cerebral ischemia.

Melatonin delivered in solid lipid nanoparticles ameliorated its neuroprotective effects in cerebral ischemia

“…These drawbacks led the researchers to continuously explore new and effective delivery systems alongside new routes of administration to deliver a therapeutic meaningful concentration to brain. Several studies have reported different innovative nano-platforms for improved oral and intranasal delivery of MLT [ [12] , [13] , [14] , [15] , [16] ]. Among others nanocarriers, lipid-based nanoparticles have been widely investigated for penetrating the intact BBB [ [17] , [18] , [19] ] as well as bypassing the BBB via direct nose-to-brain delivery of various drugs [ [20] , [21] , [22] ].…”

Non-Excitatory Amino Acids, Melatonin, and Free Radicals: Examining the Role in Stroke and Aging

“…Additionally, in a rat model of ischemia/reperfusion injury, another study found that intranasal administration of melatonin loaded in lipidic nanocapsules post-stroke can increase the number of surviving neurons in the hippocampal CA1 region and improve oxidative stress and inflammatory marker levels in the hippocampus. These effects were even more pronounced than those observed with oral melatonin administration [460].…”

Lipid nanocapsules: A Novel Strategy for Brain Targeting via Nasal Administration

“…They proved that the prepared drug loaded LNCs have lessened the in vivo glioma growth by about 81% [104]. Also, Bseiso et al concluded that melatonin loaded LNCs may be an encouraging delivery system for nose to brain delivery for the remedy of cerebral ischemia [105]. Successful preparation of melatonin loaded LNCs with suitable physicochemical properties resulted in high ex vivo nasal permeation and promising neuroprotective effects in vivo, suggesting the therapeutic potential of LNCs in lessening the effects of ischemic stroke.…”