Analogous β-Carboline Alkaloids Harmaline and Harmine Ameliorate Scopolamine-Induced Cognition Dysfunction by Attenuating Acetylcholinesterase Activity, Oxidative Stress, and Inflammation in Mice

Abstract

The analogous β-carboline alkaloids, harmaline (HAL) and harmine (HAR), possess a variety of biological properties, including acetylcholinesterase (AChE) inhibitory activity, antioxidant, anti-inflammatory, and many others, and have great potential for treating Alzheimer’s disease (AD). However, studies have showed that the two compounds have similar structures and in vitro AChE inhibitory activities but with significant difference in bioavailability. The objective of this study was to comparatively investigate the effects of HAL and HAR in memory deficits of scopolamine-induced mice. In the present study, mice were pretreated with HAL (2, 5, and 10 mg/kg), HAR (10, 20, and 30 mg/kg) and donepezil (5 mg/kg) by intragastrically for 7 days, and were daily intraperitoneal injected with scopolamine (1 mg/kg) to induce memory deficits and then subjected to behavioral evaluation by Morris water maze. To further elucidate the underlying mechanisms of HAL and HAR in improving learning and memory, the levels of various biochemical factors and protein expressions related to cholinergic function, oxidative stress, and inflammation were examined. The results showed that HAL and HAR could effectively ameliorate memory deficits in scopolamine-induced mice. Both of them exhibited an enhancement in cholinergic function by inhibiting AChE and inducing choline acetyltransferase (ChAT) activities, and antioxidant defense via increasing the antioxidant enzymes activities of superoxide dismutase and glutathione peroxidase, and reducing maleic diadehyde production, and anti-inflammatory effects through suppressing myeloperoxidase, tumor necrosis factor α, and nitric oxide as well as modulation of critical neurotransmitters such as acetylcholine (ACh), choline (Ch), L-tryptophan (L-Trp), 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (γ-GABA), and L-glutamic acid (L-Glu). Furthermore, the regulations of HAL on cholinergic function, inflammation, and neurotransmitters were more striking than those of HAR, and HAL manifested a comparable antioxidant capacity to HAR. Remarkably, the effective dosage of HAL (2 mg/kg) was far lower than that of HAR (20 mg/kg), which probably due to the evidently differences in the bioavailability and metabolic stability of the two analogs. Taken together, all these results revealed that HAL may be a promising candidate compound with better anti-amnesic effects and pharmacokinetic characteristics for the treatments of AD and related diseases.

Protective effects of Genistein on the cognitive deficits induced by chronic sleep deprivation

“…Thus, sustainable oxidative stress can eventually result in the cognitive function damage. In addition, accumulating evidence has suggested that oxidative stress plays an important role in the development of neurodegenerative disorders (Li et al, ). Although the precise underlying mechanisms for the cognitive impairment induced by SD remain elusive, it was well believed that elevated oxidative stress in the certain brain areas might be the major factor (Aleisa, Helal, Alzoubi, Tran, & Alkadhi, ; Nabaee, Kesmati, Shahriari, Khajehpour, & Torabi, ).…”

“…The method of western blotting analysis was conducted according to the previous reports (Li et al, ; Manchanda et al, ). The dissected cortical and hippocampal tissues ( n = 3 for each group) were homogenized in the radioimmunoprecipitation assay lysis buffer with protease and phosphatase inhibitor cocktail (Sigma‐Aldrich, St. Louis, MO, USA).…”

Chronic harmine treatment has a delayed effect on mobility in control and socially defeated rats

“…Harmine is metabolized in the liver into harmol and hydroxylated harmine and excreted both via the intestines and the kidneys (Zetler et al 1974;Jiang et al 2015;Zhao et al 2012). Harmine may be an interesting candidate drug as it shows not only antidepressant (Fortunato et al 2009;Réus et al 2010b;Liu et al 2017a) but also antiinflammatory properties (Liu et al 2017b;Li et al 2018).…”

Facing COVID-19 via anti-inflammatory mechanism of action: Molecular docking and Pharmacokinetic studies of six anti-inflammatory compounds derived from Passiflora edulis

“…Molecules responsible for this effect could be compounds like C-glycosyl avonoids vicenin, orientin, chrysin, vitexin and kaempferol [20]. Finally, Harmol and harmine, two uorescent harmala alkaloids showed anti-in ammatory activity by signi cantly inhibiting the NF-kB signaling pathway [21][22].…”