Effect of quercetin-loaded poly (lactic-co-glycolic) acid nanoparticles on lipopolysaccharide-induced memory decline, oxidative stress, amyloidogenesis, neurotransmission, and Nrf2/HO-1 expression

Abstract

Neuroinflammation contributes to the pathogenesis of several neurodegenerative disorders. This study examined the neuroprotective effect of quercetin (QUR)-loaded poly (lactic-co-glycolic) acid (PLGA) nanoparticles (QUR NANO) against the neurotoxicity induced by lipopolysaccharide (LPS) in mice. A QUR NANO formulation was prepared and characterized by differential scanning calorimetry, X-ray diffraction, entrapment efficiency (EE), high-resolution transmission electron microscopy, field emission scanning electron microscopy, and in vitro drug release profile. Levels of glutathione, malondialdehyde, catalase, inducible nitric oxide synthase (iNOS), amyloid beta 42 (Aβ₄₂), β-secretase, gamma-aminobutyric acid (GABA), and acetylcholine esterase (AChE) were measured in the mouse brain tissues. The gene expression of nuclear factor erythroid-related factor 2 (Nrf-2) and heme oxygenase-1 (HO-1) were also determined. The prepared QUR NANO formulation showed 92.07 ± 3.21% EE and drug loading of 4.62 ± 0.55. It exhibited clusters of nano-spherical particles with smooth surface areas, and the loading process was confirmed. In vivo, the QUR NANO preserved the spatial memory of mice and protected the hippocampus from LPS-induced histological lesions. The QUR NANO significantly reduced the levels of malondialdehyde, iNOS, Aβ₄₂, β-secretase, and AChE in brain tissue homogenates. Conversely, QUR NANO increased the glutathione, catalase, and GABA concentrations and upregulated the expression of Nrf-2 and HO-1 genes. Remarkably, the neuroprotective effect of QUR NANO was significantly greater than that of herbal QUR. In summary, the prepared QUR NANO formulation was efficient in mitigating LPS-induced neurotoxicity by reducing memory loss, oxidative stress, and amyloidogenesis while preserving neurotransmission and upregulating the expression of Nrf2 and HO-1 genes. This study addresses several key factors in neuroinflammatory disorders and explores the potential of QUR-loaded nanoparticles as a novel therapeutic approach to alleviate these factors.

Keywords: Amyloid beta; Antioxidant; Brain; Nanoparticles; Quercetin.

Fig. 1

Characterization and morphology of QUR NANO formulation. (a) The XRD patterns of PLGA, QUR, and QUR NANO. The diffracted peaks of the spectra exhibited sluggish differences in relative intensity, position, and shape over a 2 Theta range, demonstrating the success of the QUR loading process. (b) The DSC thermogram of QUR NANO. (c) In vitro drug release of QUR and QUR-loaded nanoparticles. (d) Morphology of QUR NANO formulation showing the following: (A) QUR N.P.s with uniform and spherical shape. (B) PLGA N.P.s with semi-spherical and irregular shape (C–F) H-RTEM images reveal the morphology of QUR NANO, showing clusters of spherical patterns. (G&H) FESEM images show the QUR NANO with a smooth surface area and lacking size uniformity.

Fig. 2

Effect of QUR NANO on the brain histopathological alterations and memory function. (A) The hippocampal CA1 regions of the examined groups were stained with H&E to reveal the following histological features: The negative control group showed a hippocampal region with normal gray matter, normal Purkinje cells (arrow), and nearly normal white matter (star). The LPS group showed a hippocampal region with pre-vascular edema (arrow) and pre-cellular edema (star), with nearly normal white matter. The LPS + QUR group showed a hippocampal region with a normal granular layer and mild edema in the white matter (arrow). The LPS + QUR NANO group showed a normal hippocampal region with slight vascular degeneration (arrow) and nearly normal cells. The QUR group showed a normal hippocampal region with nearly normal vasculature (arrow) and nearly normal cells (star). The QUR NANO group showed a normal hippocampal region with normal Purkinje cells (arrow). The PLGA group showed a normal hippocampal region in the gray matter, with mild congestion in a few areas (arrow). Scale bar = 100 μm. (B) Column figure shows the percentage of spontaneous alternation behavior (SAB %) in the Y-maze test among the control negative, LPS, LPS + QUR, LPS + QUR NANO, QUR, QUR NANO, and PLGA groups. The SAB % was calculated as the actual alternation/maximum alternation × 100. N = 10 animals/group. a: significant value versus the negative control group, b: significant value versus the LPS group, c: significant value versus the LPS + QUR group, d^: significant value versus the LPS + QUR NANO group.

Fig. 3

Effect of QUR NANO formulation on the oxidative stress biomarkers. Column figures show the levels of GSH, CAT, MDA, iNOS, Nrf2 fold expression, and HO-1 fold expression in the brain tissue homogenates of the negative control, LPS, LPS + QUR, LPS + QUR NANO, QUR, QUR NANO, and PLGA groups. N = 6 mice/group. a: significant value versus the negative control group, b: significant value versus the LPS group, c: significant value versus the LPS + QUR group, d^: significant value versus the LPS + QUR NANO group, e: significant value versus the QUR group, f: significant value versus the QUR NANO group.

Fig. 4

Effect of QUR NANO formulation on the brain amyloidogenesis and neurotransmission. Column figures show the levels of (A) Aβ₄₂, (B) β-secretase, (C) AChE, and (D) GABA in the studied groups. N = 6 mice/group. a: significant value versus the negative control group, b: significant value versus the LPS group, c: significant value versus the LPS + QUR group, d^: significant value versus the LPS + QUR NANO group, e: significant value versus the QUR group, f: significant value versus the QUR NANO group.