Preparation and evaluation of a non-invasive intranasal luteolin delivery for the management of cognitive dysfunction in Alzheimer’s disease (AD) using novel chitosan decorated nanoparticles. Development of luteolin-loaded chitosomes was followed by full in vitro characterization. In vivo efficacy was evaluated using a sporadic Alzheimer’s disease (SAD) animal model via intracerebroventricular injection of 3 mg/kg streptozotocin (ICV-STZ). Treatment groups of luteolin suspension and chitosomes (50 mg/kg) were then intranasally administered after 5 h of ICV-STZ followed by everyday administration for 21 consecutive days. Behavioral, histological, immunohistochemical, and biochemical studies were conducted. Chitosomes yielded promising quality attributes in terms of particle size (PS) (412.8 ± 3.28 nm), polydispersity index (PDI) (0.378 ± 0.07), Zeta potential (ZP) (37.4 ± 2.13 mv), and percentage entrapment efficiency (EE%) (86.6 ± 2.05%). Behavioral findings showed obvious improvement in the acquisition of short-term and long-term spatial memory. Furthermore, histological evaluation revealed an increased neuronal survival rate with a reduction in the number of amyloid plaques. Biochemical results showed improved antioxidant effects and reduced pro-inflammatory mediators’ levels. In addition, a suppression by half was observed in the levels of both Aβ aggregation and hyperphosphorylated-tau protein in comparison to the model control group which in turn confirmed the capability of luteolin-loaded chitosomes (LUT-CHS) in attenuating the pathological changes of AD. The prepared nanoparticles are considered a promising safe, effective, and non-invasive nanodelivery system that improves cognitive function in SAD albino mice as opposed to luteolin suspension.

The aim of the present study was to assess the neuroprotective effects of xanthotoxin and umbelliferone in streptozotocin (STZ)‐induced cognitive dysfunction in rats. Animals were injected intracerebroventricularly (ICV) with STZ (3 mg/kg) once to induce a sporadic Alzheimer's disease (SAD)‐like condition. Xanthotoxin or umbelliferone (15 mg/kg, i.p.) were administered 5 hr after ICV‐STZ and daily for 20 consecutive days. Xanthotoxin or umbelliferone prevented cognitive deficits in the Morris water maze and object recognition tests. In parallel, xanthotoxin or umbelliferone reduced hippocampal acetylcholinestrase activity and malondialdehyde level. Moreover, xanthotoxin or umbelliferone increased glutathione content. These coumarins also modulated neuronal cell death by reducing the level of proinflammatory cytokines (tumour necrosis factor‐alpha and interleukin‐6), inhibiting the overexpression of inflammatory markers (nuclear factor κB [NF‐κB] and cyclooxygenase II), and upregulating the expression of NF‐κB inhibitor (IκB‐α). Interestingly, xanthotoxin diminished phosphorylated JAK2 and phosphorylated STAT3 protein expression, while umbelliferone markedly replenished nuclear factor erythroid‐derived 2‐like 2 (Nrf2) and haem oxygenase‐1 (HO‐1) levels. The current study provides evidence for the protective effect of xanthotoxin and umbelliferone in STZ‐induced cognitive dysfunction in rats. This effect may be attributed, at least in part, to inhibiting acetylcholinestrase and attenuating oxidative stress, neuroinflammation and neuronal loss.

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Sporadic Alzheimer’s disease (AD) is the most common neurodegenerative disorder with cognitive dysfunction. Remarkably, alteration in the gut microbiome and resultant insulin resistance has been shown to be connected to metabolic syndrome, the crucial risk factor for AD, and also to be implicated in AD pathogenesis. Thus, this study, we assessed the efficiency of probiotics fermentation technology (PFT), a kefir product, in enhancing insulin signaling via modulation of gut microbiota to halt the development of AD. We also compared its effectiveness to that of pioglitazone, an insulin sensitizer that has been confirmed to substantially treat AD. AD was induced in mice by a single injection of intracerebroventricular streptozotocin (STZ; 3 mg/kg). PFT (100, 200, 400 mg/kg) and pioglitazone (30 mg/kg) were administered orally for 3 weeks. Behavioral tests were conducted to assess cognitive function, and hippocampal levels of acetylcholine (Ach) and β-amyloid (Aβ1–42) protein were assessed along with histological examination. Moreover, the expression of the insulin receptor, insulin degrading enzyme (IDE), and the phosphorylated forms of phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), glycogen synthase kinase-3β (GSK-3β), mammalian target of rapamycin (mTOR), and tau were detected. Furthermore, oxidative stress and inflammatory biomarkers were estimated. Treatment with PFT reversed STZ-induced neurodegeneration and cognitive impairment, enhanced hippocampal Ach levels, and reduced Aβ1–42 levels after restoration of IDE activity. PFT also improved insulin signaling, as evidenced by upregulation of insulin receptor expression and activation of PI3K/Akt signaling with subsequent suppression of GSK-3β and mTOR signaling, which result in the downregulation of hyperphosphorylated tau. Moreover, PFT significantly diminished oxidative stress and inflammation induced by STZ. These potential effects were parallel to those produced by pioglitazone. Therefore, PFT targets multiple mechanisms incorporated in the pathogenesis of AD and hence might be a beneficial therapy for AD.

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is characterized by amyloid deposition and neurofibrillary tangles formation owing to tau protein hyperphosphorylation. Intra-cerebroventricular (ICV) administration of streptozotocin (STZ) has been widely used as a model of sporadic AD as it mimics many neuro-pathological changes witnessed in this form of AD. In the present study, mangostanaxanthone IV (MX-IV)-induced neuro-protective effects in the ICV-STZ mouse model were investigated. STZ (3 mg/kg, ICV) was injected once, followed by either MX-IV (30 mg/kg/day, oral) or donepezil (2.5 mg/kg/day, oral) for 21 days. Treatment with MX-IV diminished ICV-STZ-induced oxidative stress, neuro-inflammation, and apoptosis which was reflected by a significant reduction in malondialdehyde (MDA), hydrogen peroxide (H2O2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) brain contents contrary to increased glutathione (GSH) content. Moreover, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase content and cleaved caspase-3 activity were reduced together with a marked decrement in amyloid plaques number and phosphorylated tau expression via PI3K/Akt/GSK-3β pathway modulation, leading to obvious enhancement in neuronal survival and cognition. Therefore, MX-IV is deemed as a prosperous nominee for AD management with obvious neuro-protective effects that were comparable to the standard drug donepezil.

Systemic treatments for rheumatoid arthritis are associated with many side effects. This study aimed to minimize the side effects associated with the systemic administration of leflunomide (LEF) by formulating LEF-loaded emulsomes (EMLs) for intra-articular administration. Additionally, EMLs were loaded with supramagnetic nanoparticles (SPIONs) to enhance joint localization, where a magnet was placed on the joint area after intra-articular administration. Full in vitro characterization, including colloidal characteristics, entrapment efficiency, and in vitro release were conducted besides the in vivo evaluation in rats with adjuvant-induced arthritis. In vivo study included joint diameter measurement, X-ray radiographic analysis, RT-PCR analysis, Western blotting, ELISA for inflammatory markers, and histopathological examination of dissected joints. The particle size and entrapment efficiency of the selected LEF SPION EMLs were 198.2 nm and 83.7%, respectively. The EMLs exhibited sustained release for 24 h. Moreover, in vivo evaluation revealed LEF SPION EMLs to be superior to the LEF suspension, likely due to the increase in LEF solubility by nanoencapsulation that improved the pharmacological effects and the use of SPION that ensured the localization of EMLs in the intra-articular cavity upon administration.