The Role of Melatonin on Behavioral Changes and Concomitant Oxidative Stress in icvAβ1-42 Rat Model with Pinealectomy

Abstract

One of the pathological hallmarks of Alzheimer’s disease (AD) associated with its progression that contributes to β-amyloid (Aβ) generation is oxidative stress (OS). Clinical data suggest that melatonin is a potent antioxidant that might be effective in the adjunctive therapy of this neurodegenerative disease. The present study aimed to explore the role of melatonin on behavioral changes and markers of OS in three rat models, namely, pinealectomy (pin) model of melatonin deficit, intracerebroventricular (icv)Aβ1-42 model of AD, and combination of both pin and Aβ1-42 model (pin+icvAβ1-42). The chronic injection with vehicle/melatonin (50 mg/kg, i.p. for 40 days) started on the same day of sham/pin and icv vehicle/Aβ1-42 infusion procedures. Anxiety in the open field and the elevated plus-maze test and cognitive responses in the object recognition test were tested between the 30th–35th day after the surgical procedures. Markers of OS in the frontal cortex (FC) and hippocampus were detected by the ELISA method. Melatonin treatment corrected the exacerbated anxiety response only in the pin+icvAβ1-42 model while it alleviated the cognitive impairment in the three models. Pinealectomy disturbed the antioxidant system via enhanced SOD activity and decreased GSH levels both in the FC and hippocampus. The Aβ1-42 model decreased the SOD activity in the FC and elevated the MDA level in the two brain structures. The pin+icvAβ1-42 model impaired the antioxidant system and elevated lipid peroxidation. Melatonin supplementation restored only the elevated MDA level of icvAβ1-42 and pin+icvAβ1-42 model in the hippocampus. In conclusion, our study reveals that the pin+icvAβ1-42 rat model triggers more pronounced anxiety and alterations in markers of OS that may be associated with melatonin deficit concomitant to icvAβ1-42-induced AD pathology.

The Vital Role of Melatonin and Its Metabolites in the Neuroprotection and Retardation of Brain Aging

“…Exogenous melatonin administration (50 mg/kg, i.p. for 40 days) was able to mitigate the cognitive decline in pinealectomized (pin) adult Sprague Dawley rats, Aβ1-42 icv injected rats, and a combination of both a pin and Aβ1-42 (pin+Aβ1-42)-treated rat model, whereas it could correct the elevated anxiety only in the pin+Aβ1-42 model [166]. As a result, long-term melatonin administration alleviates behavioral and cognitive deficits and reduces Aβ aggregation and deposition, probably through promoting Aβ clearance via glymphatic drainage [167][168][169][170][171].…”

“…The antioxidant activities of the widely known hormone melatonin and its brain metabolite AMK are well studied and documented in a lot of experimental research papers on the topic of neurodegeneration. As a mitochondrially targeted robust antioxidant and scavenger of toxic free radicals, melatonin mitigates oxidative stress in the brain [164,166,[177][178][179][180][181][182]. Decreased oxidative stress markers were also measured in patients with Parkinson's disease [183] and amyotrophic lateral sclerosis [184], after melatonin administration.…”

Protective Effect of the Novel Melatonin Analogue Containing Donepezil Fragment on Memory Impairment via MT/ERK/CREB Signaling in the Hippocampus in a Rat Model of Pinealectomy and Subsequent Aβ1-42 Infusion

“…The pineal ablation gland in rodents has been accepted as a relevant model to study the detrimental effects of melatonin deficiency, which resemble the signaling dysfunction associated with neurodegenerative diseases, including AD [14]. Recently, we reported that simultaneous removal of the pineal gland and intracerebroventricular (icv) infusion of Aβ 1-42 exacerbated behavioral responses and concomitant oxidative stress in the hippocampus and the frontal cortex [15]. Our research team synthesized and tested a series of new melatonin analogues and sulfonyl hydrazone compounds with a melatonin scaffold [16].…”

Intestinal melatonin levels and gut microbiota homeostasis are independent of the pineal gland in pigs

“…PINX was performed on an endogenous MEL deficiency model to evaluate the regulation of circadian rhythms in the pineal gland (de Farias et al, 2015 ; Tchekalarova et al, 2020 ), immunity (Sahin et al, 2018 ; Luo et al, 2020 ), Alzheimer's disease (Tzoneva et al, 2021 ), and inflammation and oxidative stress (Ballur et al, 2022 ). However, most of these studies were performed on rodents (Al Gburi et al, 2022 ; Demir et al, 2022 ), so it is difficult to use the findings of these studies to explain various MEL deficiency disorders in humans because nocturnal rodents and diurnal humans have different circadian rhythms in terms of behavior and physiology (Cheung et al, 2005 ; Slawik et al, 2016 ).…”