Deciphering the Potential Neuroprotective Effects of Luteolin against Aβ1–42-Induced Alzheimer’s Disease

Abstract

The current study was undertaken to unveil the protective effects of Luteolin, a natural flavonoid, against amyloid-beta (Aβ1–42)-induced neuroinflammation, amyloidogenesis, and synaptic dysfunction in mice. For the development of an AD mouse model, amyloid-beta (Aβ1–42, 5 µL/5 min/mouse) oligomers were injected intracerebroventricularly (i.c.v.) into mice’s brain by using a stereotaxic frame. After that, the mice were treated with Luteolin for two weeks at a dose of 80 mg/kg/day. To monitor the biochemical changes, we conducted western blotting and immunofluorescence analysis. According to our findings, the infusion of amyloid-beta activated c-Jun N-terminal kinases (p-JNK), p38 mitogen-activated protein kinases, glial fibrillary acidic protein (GFAP), and ionized calcium adaptor molecule 1 (Iba-1) in the cortex and hippocampus of the experimental mice; these changes were significantly inhibited in Aβ1–42 + Luteolin-treated mice. Likewise, we also checked the expression of inflammatory markers, such as p-nuclear factor-kB p65 (p-NF-kB p65 (Ser536), tissue necrosis factor (TNF-α), and Interleukin1-β (IL-1β), in Aβ1–42-injected mice brain, which was attenuated in Aβ1–42 + Luteolin-treated mice brains. Further, we investigated the expression of pro- and anti-apoptotic cell death markers such as Bax, Bcl-2, Caspase-3, and Cox-2, which was significantly reduced in Aβ1–42 + Lut-treated mice brains compared to the brains of the Aβ-injected group. The results also indicated that with the administration of Aβ1–42, the expression levels of β-site amyloid precursor protein cleaving enzyme (BACE-1) and amyloid-beta (Aβ1–42) were significantly enhanced, while they were reduced in Aβ1–42 + Luteolin-treated mice. We also checked the expression of synaptic markers such as PSD-95 and SNAP-25, which was significantly enhanced in Aβ1–42 + Lut-treated mice. To unveil the underlying factors responsible for the protective effects of Luteolin against AD, we used a specific JNK inhibitor, which suggested that Luteolin reduced Aβ-associated neuroinflammation and neurodegeneration via inhibition of JNK. Collectively, our results indicate that Luteolin could serve as a novel therapeutic agent against AD-like pathological changes in mice.

Luteolin Treatment Ameliorates Brain Development and Behavioral Performance in a Mouse Model of CDKL5 Deficiency Disorder

“…Moreover, in line with evidence that treatment with luteolin ameliorated social behaviors in a murine model of autistic behaviors [ 47 ], we found a marked improvement in motor stereotypies and hyperactivity phenotype in treated- Cdkl 5 +/− mice, abnormalities that are linked to autistic-like behaviors, suggesting the therapeutic efficacy of luteolin in other brain regions besides the hippocampus. Since it has been well documented that chronic treatment with luteolin does not affect behavior in wild-type mice [ 41 , 64 , 65 , 66 ], the effect of luteolin on the Cdkl5 −/+ mouse might be explained by the selective recovery of microglia overactivation exerted by luteolin in the Cdkl5 KO condition. This is in line with recent evidence suggesting that microglial activation contributes to cognitive and motor impairments in mouse models of brain disorders [ 67 , 68 , 69 ].…”

Natural and Semi-Synthetic Flavonoid Anti-SARS-CoV-2 Agents for the Treatment of Long COVID-19 Disease and Neurodegenerative Disorders of Cognitive Decline

“…Luteolin's anti-oxidant, anti-inflammatory properties and ability to induce Nrf2 are neuroprotective [214,215] and counter neuroinflammation following brain trauma [216] downregulating the TLR4/TRAF6/NF-κB pathway after intracerebral hemorrhage and cerebral ischemia [217,218].…”

Medicinal Herbs and Their Derived Ingredients Protect against Cognitive Decline in In Vivo Models of Alzheimer’s Disease

“…Reactive oxygen species (ROS)-induced oxidative stress elicited in the early stages of AD is closely associated with Aβ generation, which leads to synaptic dysfunction and cognitive impairment [ 22 , 44 ]. Superoxide anions, hydroxyl radicals, and hydrogen peroxide are crucial ROS types, which attack intracellular DNA, proteins, and lipids.…”

“…Moreover, the extent of p-tau aggregation in the hippocampus reveals a close relationship of p-tau with cognitive function [ 65 ]. ERK1/2 and phosphoinositide 3 kinase (PI3K)/protein kinase B (Akt), which are upstream factors of GSK-3β, inhibit GSK-3β activity through the phosphorylation of GSK-3α at Ser21 and GSK-3β at Ser9, resulting in the suppression of p-tau-induced neuronal injury [ 17 , 44 , 66 , 67 ]. Sulforaphene, from Raphani semen , inhibits p-tau accumulation partly by upregulating Akt (Ser473)/GSK-3β (Ser9)–mediated signaling in the hippocampus at 6 weeks after STZ-induced AD [ 64 ].…”

“…MAPKs regulate apoptotic signaling through the modulation of Bcl-2 family members in AD animal models [ 44 ]. Bcl-2 family proteins, including pro-apoptotic proteins [i.e., Bcl-2-associated x protein (Bax), Bcl-2 antagonist killer 1 (Bak), and Bcl-2-associated death promoter (Bad)] and anti-apoptotic proteins (i.e., Bcl-2, Bcl-xL, and myeloid cell leukemia 1), rigorously regulate mitochondrial outer membrane (MOM) integrity and permeability [ 13 ].…”