Inhibitory effects of short-term administration of dl-α-lipoic acid on oxidative vulnerability induced by Aβ amyloid fibrils (25–35) in mice

Abstract

Abeta amyloid peptide is believed to induce oxidative stress leading to inflammation, which is postulated to play a significant role in the toxicity of Alzheimer's disease (AD). This study was designed to investigate the inhibitory effects of DL-alpha lipoic acid (LA), a potential free radical scavenger, on oxidative vulnerability induced by intraperitoneal injection of Abeta25-35 amyloid fibrils in mice. Mice were divided into three groups: control, Abeta amyloid toxicity induced (AT), and LA treated (ATL). Blood Plasma was separated, liver, spleen and brain were dissected and analysis of oxidants, antioxidants, ATPases, glial fibrillary acidic protein (GFAP) and nuclear factor kappa-B (NFkappaB) were carried out. Results show biochemical parameters such as reactive oxygen species (ROS) and lipid peroxidation (LPO) were significantly lowered (P < 0.05) and levels of antioxidants and ATPase (P < 0.05) were significantly increased (P < 0.05) in hepatocytes, splenocytes and astrocytes of the ATL group. Moreover, our histological results revealed a decreased GFAP immunoreactivity in the neocortical region and NFkappaB immunoreactivity in neocortex, liver and spleen. This study reiterates LA as a potent free radical scavenger to combat oxidative vulnerability in the treatment for Abeta amyloid toxicity.

Tacrine-6-Ferulic Acid, a Novel Multifunctional Dimer, Inhibits Amyloid-β-Mediated Alzheimer's Disease-Associated Pathogenesis In Vitro and In Vivo

“…We found that T6FA (10–25 µM) remarkably inhibited the auto-aggregation of Aβ (Figure 3). Given the toxicity of Aβ is mainly mediated by the prefibrillar oligomers of Aβ and Aβ-induced ROS [5]–[8], we hypothesized that T6FA could block the Aβ-induced cell death through its anti-oxidant activity and anti-aggregation.…”

“…Free-radical oxidative stress, particularly of neuronal lipids, proteins and DNA, is extensive in those AD brain areas in which Aβ is abundant and even those mild cognitive impairment brains [5]–[8], [37]. Our previous research demonstrated that T6FA has antioxidant activity determined by scavenging stable DPPH radicals [17], [19].…”

“…Interestingly, novel ferulic acid and benzothiazole dimer derivatives have been found to specifically bind to Aβ fibrils (fAβ) and to inhibit fibril aggregation as FA [22]–[23]. These results suggest that tacrine-ferulic acid hybrids might also inhibit the fibril aggregation of Aβ and Aβ-mediated toxicity, potential targets for AD therapy [5]–[8].…”

“…The majority of therapeutic strategies and drug development approaches for AD were based on dysfunction of acetylcholine to date, which mainly improves the pathological symptom [4]. Inhibition of Aβ fibril aggregation and antioxidants are also viewed as promising strategies to halt the progression of AD [5]–[8]. Unfortunately, current “one-molecule-one-target” drugs are not effective strategy to delay or block the progress of AD pathology because of multiple causes, such as cholinergic deficiency, Aβ and tau protein toxicity, oxidative stress and so on.…”

Promoter polymorphisms which modulate BACE1 expression are associated with sporadic Alzheimer's disease

“…Following transfection for 24 hr, Ab 25-35 was added into the normal 1640 medium at 0.015 mM concentration to model pathology of AD; serum deprivation that serum-free 1640 substituted the normal 1640 produced energy starvation and apoptosis. Here we use Ab 25-35 , a toxic antigenic fragment which exhibits all the biological activity of the full length Ab and has been earlier used by other researchers to study the neuronal toxicity and oxidative vulnerability [Jesudason et al, 2008]. Ab 25-35 is a convenient tool for the investigation of neurotoxic mechanisms involved in AD [Frozza et al, 2009].…”