The therapeutic potential of ellagic acid loaded in nanocarriers for the treatment of the Alzheimer’s disease

Abstract

AbstractBackgroundEllagic acid (EA) has been shown to have protective effects on Alzheimer’s disease, but it shows poor pharmacokinetic profile. A valid approach is delivering the drug in non‐ionic surfactant vesicles (NBVs) through the nose to brain (N2B) route coupled to focused ultrasound (FUS) improving brain targeting. Several niosomal formulations composed by specific surfactants (potentially enhance neuroprotective effect) have been characterized. The contrast agent was loaded inside the nanocarriers which was subsequently characterized using FUS in vitro technique. The EA will be loaded inside the vesicles and the neuroprotective effect of NBVs and EA‐NBVs will be explored using electrophysiological recordings (field and whole cell patch clamp) of hippocampal synaptic transmission and plasticity in ex‐vivo Alzheimer model.MethodEmpty and loaded NBVs were prepared and deeply characterized. In vitro FUS analysis were performed to evaluate the ability of FUS to induce a stable and prolonged release of probe‐drug loaded. The electrophysiological experiments were conducted using C57BL6/J mice of both sexes aged between 30 and 40 days. We performed electrophysiological recordings in area CA1‐CA3. Paired pulse facilitation was assessed at inter‐stimulus intervals ranging from 50 to 500 ms. An additional recording of baseline was evaluated before inducing Long‐Term Potentiation (LTP) by theta‐burst stimulation. Responses (fEPSP) were recorded for 1 hour after tetanization. In vitro Alzheimer model was obtained applying Aβ1‐42 oligomers (200 nM). As a control, we tested the effect of Aβ1‐42 with a scrambled sequence applied in the same condition of Aβ1‐42. Empty and loaded NBVs were used in presence and not of Aβ1‐42 and of Aβ1‐42 scrambled.ResultPreliminary results of empty and loaded NBVs present an optimal range of size for N2B delivery and in vitro FUS release shows a stable and controlled release profile of loaded drug. Slices incubated in presence of Aβ1‐42 showed an impairment of LTP, while this effect didn’t occur after incubation of slices with Aβ1‐42 scrambled. Preliminary results show that NBVs formulations didn’t compromise LTP suggesting the possibility of using them as drug carriers in Alzheimer’s disease.ConclusionA better brain delivery of EA could be a valid approach in pathologies characterized by synaptic dysfunction.