Nose-to Brain Delivery of Resveratrol, a Non-Invasive Method for the Treatment of Cerebral Ischemia

Abstract

Cerebral ischemia represents a particular condition among neurological diseases due to its high frequency, high associated mortality, and the permanent disability in patients that survive it. Numerous studies in animal models have demonstrated the protective properties of resveratrol against cerebral ischemia. Resveratrol is a soluble molecule in polar solvents with high membrane permeability; however, it is rapidly metabolized at the liver and is also a substrate of the ATP binding cassette transporters located at the blood–brain barrier. These circumstances reduced bioavailability of resveratrol to the brain. In this review, we examined nasal resveratrol’s formulations including nanocarriers such as nanostructured lipid carriers, nanoemulsions, nanoparticles, bilosomes, cubosomal, and transferosomes that are directly transported to the brain. An intranasal administration route evades resveratrol transformation due to liver metabolism. Components of nanoformulations increased resveratrol absorption to the brain by enhancing permeation through specific approaches and also maintaining stability during storage. Both characteristics improved the delivery of resveratrol with conserved antioxidant capacity and protective properties for neurological models. Although demonstration that the nanoformulations prevents resveratrol’s blood–brain barrier retention is missing, properties of resveratrol’s nanoformulation encourage testing in clinical trials; however, regulatory approval for a novel nanocarrier in nasal drug delivery is complicated and needs approval.

Introduction

Resveratrol (3, 5, 40-trihydroxystilbene) is a natural polyphenol produced in many plants (e.g., grapes, peanuts, and hops) as a defense molecule against microbial infections and physical injury [1] (Figure 1). In plants, the content of resveratrol is limited, therefore, to achieve commercial purposes, it has been obtained from Japanese knotweed and grape skins and seeds, which has been reported to have a high content (ranging from 2 to 13 mg/L). Also, due to resveratrol’s multiple pharmacological activities found in humans, alternative methods to obtain larger amounts of resveratrol have been implemented, like chemical synthesis and biotechnological approaches, such as tissue culture and genetic engineering [2].

Table 1. Nanotechnology-based formulations for resveratrol delivery.

Stroke is placed as the second leading cause of global death, with a high number of survivors being permanently incapacitated. Interestingly, the statistics have been changing: stroke was considered a disease of the developed world, nevertheless, the burden of stroke seems to be shifting to the developing countries, somewhat due to poor community information of stroke notice signs (which is the main cause of delay in arrival to the hospital). A wide range of stroke risk factors have been recognizably responsible for 90% of all strokes, among them, age is the strongest determinant, since age doubles the risk of stroke every decade above the age of 55 years. Regrettably, individuals who survive stroke live with a profound effect on health-related quality of life [3]. Generally, stroke is classified as an ischemic stroke, caused by interruption of the blood supply to a specific region of the brain (the most common type) and hemorrhagic stroke, attributed to the rupture of a blood vessel. In an ischemic stroke, the reduction of the steady blood flow provokes hypoxia and hypoglycemia that leads to severe affection to brain cell function. Typical treatment for ischemic stroke is the restoration of blood flow/oxygenation to the brain in a timely fashion by thrombolysis, using the intravenous recombinant tissue-type plasminogen activator, or by mechanical thrombectomy [4]. Paradoxically, reperfusion therapy after a prolong period of ischemia (>3 h) often leads to further cerebral damage. Ischemia and reperfusion activates a cascade of events including excitotoxicity, driven by the excessive activation of N-methyl-D-Aspartate glutamate receptors; oxidative stress, associated with mitochondrial dysfunction and the increase of reactive oxygen species production; the inflammatory response, which can cause damage due to high concentrations of inflammatory mediators; autophagy, a type of cell death induced by organelle damage and extracellular injury stimulation; and the blood–brain barrier (BBB) breakdown process, initiated by the deterioration of thigh junction proteins at the endothelial cells and aggravated by inflammation [5,6,7].

Unfortunately, establishing an effective treatment for stroke has been unfavorable; therefore, it is indispensable to continue the study of compounds that alleviate the damage induced in animal models in future clinical studies.
The ineffectiveness of pharmacological therapies in the clinical setting may stem from the omission of significant comorbidities, such as aging, in experimental models. Notably, the limitations of drugs exhibiting protective effects in the preclinical phase involve issues of bioavailability and challenges in crossing the BBB. Considering that the majority of strokes occur in elderly patients [8], it is crucial to recognize that drug absorption in the brain undergoes age-related changes. For instance, a key transport mechanism frequently employed for drug delivery to the brain, transcytosis through the transferrin receptor, is compromised during the aging process [9]. Additionally, in murine models of aging, an observed increase in certain efflux transporters poses a significant obstacle to the efficient delivery of drugs to the brain [10]. Not surprisingly, the combination of these mechanisms leads to dramatically low net delivery fluxes of resveratrol to the brain. This is particularly relevant when attempting to reverse brain damage following cerebral infarction in patients undergoing aging processes.

Table 2. Formulations for resveratrol intranasal delivery to the brain.

Therefore, it is imperative to develop a biocompatible formulation that operates autonomously from the expression of endogenous transport systems and can effectively traverse natural barriers, even in the presence of aging processes. For that reason, the design of intranasal formulations of materials that fusion with membranes is currently seen as a promissory alternative for its use in clinical studies; this route allows direct transport to the brain from the nasal cavity along the olfactory and trigeminal nerves, hence, it is a critical step that will facilitate the delivery of the drugs to the brain.

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Alquisiras-Burgos, I.; González-Herrera, I.G.; Alcalá-Alcalá, S.; Aguilera, P. Nose-to Brain Delivery of Resveratrol, a Non-Invasive Method for the Treatment of Cerebral Ischemia. Drugs Drug Candidates 2024, 3, 102-125. https://doi.org/10.3390/ddc3010007

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