Paeonol Ameliorates Cognitive Deficits in Streptozotocin Murine Model of Sporadic Alzheimer’s Disease via Attenuation of Oxidative Stress, Inflammation, and Mitochondrial Dysfunction

Abstract

Intracerebroventricular (ICV) microinjection of diabetogenic drug streptozotocin (STZ) in rodents consistently produces a model of sporadic Alzheimer's disease (sAD) which is characterized by tau pathology and concomitant cognitive decline, insulin resistance, neuroinflammation, oxidative stress, and mitochondrial malfunction. Paeonol is an active phenolic component in some medicinal plants like Cortex Moutan with neuroprotective efficacy via exerting anti-inflammatory and antioxidative effects. This study was conducted to assess beneficial effect of paeonol in amelioration of cognitive deficits in ICV STZ rat model of sAD. STZ (3 mg/kg) was microinjected into the lateral ventricles on days 0 and 2, and paeonol was given p.o. at two doses of 25 (low) or 100 (high) mg/kg from day 0 (post-surgery) till day 24 post-STZ. Cognitive performance was evaluated in different tasks, and oxidative stress-and inflammation-related parameters were measured in addition to immunohistochemical assessment of glial fibrillary acidic protein (GFAP) as a marker of astrocytes. Paeonol at the higher dose ameliorated cognitive deficits in Barnes maze, novel object recognition (NOR) task, Y maze, and passive avoidance test. In addition, paeonol partially reversed hippocampal malondialdehyde (MDA), reactive oxygen species (ROS), total antioxidant capacity (TAC), superoxide dismutase (SOD), catalase, glutathione reductase, tumor necrosis factor α (TNFα), interleukin 6 (IL-6), mitochondrial membrane potential (MMP), myeloperoxidase (MPO), and acetylcholinesterase (AChE) activity. Paeonol treatment was also associated with lower hippocampal immunoreactivity for GFAP. This study showed that paeonol can alleviate cognitive disturbances in ICV STZ rat model of sAD via ameliorating neuroinflammation, oxidative stress, mitochondrial dysfunction, and also through its attenuation of astrogliosis.

Paeonol Derivative, 6′-Methyl Paeonol, Attenuates Aβ-Induced Pathophysiology in Cortical Neurons and in an Alzheimer’s Disease Mice Model

“…Paeonol has been shown to be able to inhibit oxidative stress-induced neuronal damage and microglia-mediated inflammation, to mediate the RhoA/Rock2 pathway, attenuating the loss of neuronal dendritic spines and to increase the frequency of spontaneous excitatory postsynaptic currents and miniature excitatory postsynaptic currents . Paeonol has also been found to inhibit the impairment of AD related behaviors in animal models. − Our results on paeonol have not only verified the compound’s AD-related activities, revealing more details regarding its molecular/cellular mechanism, but we have also showed that the compound has efficacy on our platform to prevent Aβ-induced depolarization. After modification of the structure of paeonol by adding methyl/hydroxyl groups, 6′-methyl paeonol is more effective than paeonol on the AMPA-induced abnormalities present in primary neurons.…”

“…The half maximal inhibitory concentration (IC 50 ) of paeonol based on the survival of glutamatergic neurons can not be determined thus far because the drug seems to have no effect even at 1 mM (Figure B). The effect of paeonol on AD has not been studied to a great extent and what research there is has mainly focused on its antioxidant effects ,, and effects at the organism level . We investigated this compound further by creating derivatives in addition to exploring its mechanism of action in more detail.…”

“…An extract from the root of the medicinal plant Paeonia lactiflora tastes sour; furthermore, it has been shown to modulate homeostasis . The extract, which contains the compound paeonol, has been investigated in relation to the treatment of AD, and the results mainly show amelioration of cognitive deficits in AD disease models. − Thus far, there are few reports which develop the various paeonol derivatives to investigate their roles in the treatment of AD. − In this study, we use a drug screening platform to search for herbal compounds that are able to ameliorate Aβ oligomers-induced pathophysiology. We targeted compounds extracted from P.…”

Protective mechanism of Paeonol on central nervous system

“…In terms of anti‐neuronal apoptosis, Pae inhibited the expression of caspase‐3 in the hippocampus and cortex of model rats and also restored the expression of BDNF and insulin‐like growth factor 1 (IGF‐1) to play a protective role in cognitive function (Liu, Feng, et al, 2013). Pae can reduce the levels of MDA and ROS in hippocampus and downregulate the proinflammatory factors myeloperoxidase (MPO), TNF‐α and IL‐6 expression in AD rats caused by diabetes, and the inhibition of astrocyte proliferation (Tayanloo‐Beik et al, 2022). In terms of improving diabetes, Pae prevented the weight loss of model rats, and high‐dose Pae reduced the blood sugar level and the content of advanced glycation end products, their receptors and glycosylated serum protein in DE rats, but the effect was not as good as the positive control drug aminoguanidine.…”

Cognitive Impairment in Diabetes Mellitus and Its Management by Transcription Factor Nrf2-Mediated Antioxidant Defense System

“…The dysfunctional metabolism of blood glucose damages the basilar membranes of capillaries leading to a narrowed cavity in the cerebra, thus decreasing blood supply to the brain and resulting in oxygen-free radical injury [21]. Oxidative stress is observed in cognitive impairment by increased levels of reactive oxygen species (ROS) and malondialdehyde (MDA), and decreased phase II antioxidant enzymes activities of glutathione peroxidase (GPx), chloramphenicol acetyltransferase (CAT) and superoxide dismutases (SOD) [22,23]. The brain is highly susceptible to such oxidative damage partially due to its high oxygen demand, and the fact that high amounts of polyunsaturated fatty acids are easily targeted by free radicals [24].…”