Autophagy regulates the release of exercise factors and their beneficial effects on spatial memory recall

Khoury, Reine; Saad, Joelle; Jabre, Vanessa; Ghayad, Litsa Maria; Khalifeh, Mohamad; Houbeika, Rouba; Ahmad, Perla El; Mezher, Amar; Masri, Diala El; Haddad, Zena; Eid, Fady; Barmo, Nour; Nasrallah, Patrick; Stephan, Joseph S.

doi:10.1016/j.heliyon.2023.e14705

Cited by 5 publications

(3 citation statements)

References 59 publications

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“…Also, on the AMPK pathway, metformin inhibits mTOR complex 1 (mTORC1) and favors autophagy (increases the concentration of beclin-1, the protein important in the formation and maturation of the autophagosome ATG5, the protein involved in the formation of autophagy vesicles) [ 110 , 111 ]. Autophagy is important for memory formation in hippocampus neurons [ 112 , 113 ]. Therefore, the mitigation of the negative effects of haloperidol by metformin is due to a combination of antioxidant, anti-inflammatory factors, mTOR inhibitors, and autophagy promoters, with AMPK at the center of them.…”

Section: Discussionmentioning

confidence: 99%

Drug Repurposing of Metformin for the Treatment of Haloperidol-Related Behavior Disorders and Oxidative Stress: A Preliminary Study

Jîtcă,

Gáll,

Jîtcă

et al. 2024

Pharmaceutics

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A particular attribute of the brain lies in the ability to learn, acquire information from the environment, and utilize the learned information. Previous research has noted that various factors (e.g., age, stress, anxiety, pathological issues), including antipsychotic medications, affect the brain and memory. The current study aimed to reveal the effects of chronic metformin treatment on the cognitive performance of rats and on commonly measured markers for oxidative stress. Wistar male rats (n = 40) were randomly divided into four groups: CTR (n = 10)–control group, METF (n = 10)–animals receiving metformin 500 mg/kg, HAL (n = 10)–animals receiving haloperidol 2 mg/kg, and HALMETF (n = 10)–animals receiving haloperidol 2 mg/kg and metformin 500 mg/kg. The medication was administered daily by oral gavage for 40 days. Memory and learning were assessed using the Morris Water Maze (MWM) test. At the end of the MWM, the rodents were decapitated under anesthesia, and the brain and blood samples were assayed by liquid chromatography for markers of oxidative stress (malondialdehyde, MDA, reduced/oxidized glutathione ratio, GSH/GSSG). The quantification of brain-derived neurotrophic factor (BDNF) was performed using the conventional sandwich ELISA technique. In the HALMETF group, metformin attenuated the negative effects of haloperidol. Brain and plasma MDA levels increased in the HAL group. Brain and plasma GSH/GSSG ratios and BDNF levels did not reveal any differences between groups. In conclusion, metformin treatment limits the deleterious cognitive effects of haloperidol. The effect on oxidative stress markers may also point toward an antioxidant-like effect of metformin, but this needs further tests for confirmation.

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Section: Discussionmentioning

confidence: 99%

Drug Repurposing of Metformin for the Treatment of Haloperidol-Related Behavior Disorders and Oxidative Stress: A Preliminary Study

Jîtcă,

Gáll,

Jîtcă

et al. 2024

Pharmaceutics

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“…Synaptic plasticity is involved in brain network reconstruction and clinical recovery after brain injury ( Bassi et al, 2019 ; Bettio et al, 2019 ). Different forms of exercise, such as running, light activity, and aerobic exercise, can regulate synaptic plasticity, improve cognition, and enhance spatial learning and memory ( Brockett et al, 2015 ; Khoury et al, 2023 ). Research shows that during active movement in mice, the liver can release β -hydroxybutyrate, which inhibits the deacetylation of histone acetyltransferase and increases BDNF levels in the hippocampus, thereby promoting synaptic plasticity ( Byun et al, 2023 ).…”

Section: A New Perspective On Exercise Therapy For Chronic Low Back P...mentioning

confidence: 99%

Exercise-induced neuroplasticity: a new perspective on rehabilitation for chronic low back pain

Zou,

Hao

2024

Front. Mol. Neurosci.

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Chronic low back pain patients often experience recurrent episodes due to various peripheral and central factors, leading to physical and mental impairments, affecting their daily life and work, and increasing the healthcare burden. With the continuous advancement of neuropathological research, changes in brain structure and function in chronic low back pain patients have been revealed. Neuroplasticity is an important mechanism of self-regulation in the brain and plays a key role in neural injury repair. Targeting neuroplasticity and regulating the central nervous system to improve functional impairments has become a research focus in rehabilitation medicine. Recent studies have shown that exercise can have beneficial effects on the body, such as improving cognition, combating depression, and enhancing athletic performance. Exercise-induced neuroplasticity may be a potential mechanism through which exercise affects the brain. This article systematically introduces the theory of exercise-induced neuroplasticity, explores the central effects mechanism of exercise on patients with chronic low back pain, and further looks forward to new directions in targeted neuroplasticity-based rehabilitation treatment for chronic low back pain.

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“…Postmortem human studies of individuals with depression and/or who have died by suicide show reduced BDNF protein levels in the hippocampus and other brain regions, contrary to individuals receiving antidepressant treatment ( Chen et al, 2001 ; Duman and Monteggia, 2006 ; Kim et al, 2007 ). In humans, aerobic exercise training triggers a rise in serum BDNF levels, which is linked to the increase of hippocampal volume, enhancement of spatial memory ( Erickson et al, 2011 ; Khoury et al, 2023 ), and a reduction of depressive symptoms ( Erickson et al, 2012 ). However, exercise-induced neuronal plasticity is inhibited in mice with the single nucleotide polymorphism (SNP) in the BDNF gene Val66Met (BDNF Met/Met ) ( Hariri et al, 2003 ), or when the BDNF signaling is blocked ( Vaynman et al, 2004 ).…”

Section: Physical Exercise In Alleviating Symptoms Of Major Depressionmentioning

confidence: 99%

Running from stress: a perspective on the potential benefits of exercise-induced small extracellular vesicles for individuals with major depressive disorder

Khoury

Nagy

2023

Front. Mol. Biosci.

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Aerobic exercise promotes beneficial effects in the brain including increased synaptic plasticity and neurogenesis and regulates neuroinflammation and stress response via the hypothalamic-pituitary-adrenal axis. Exercise can have therapeutic effects for numerous brain-related pathologies, including major depressive disorder (MDD). Beneficial effects of aerobic exercise are thought to be mediated through the release of “exerkines” including metabolites, proteins, nucleic acids, and hormones that communicate between the brain and periphery. While the specific mechanisms underlying the positive effects of aerobic exercise on MDD have not been fully elucidated, the evidence suggests that exercise may exert a direct or indirect influence on the brain via small extracellular vesicles which have been shown to transport signaling molecules including “exerkines” between cells and across the blood-brain barrier (BBB). sEVs are released by most cell types, found in numerous biofluids, and capable of crossing the BBB. sEVs have been associated with numerous brain-related functions including neuronal stress response, cell-cell communication, as well as those affected by exercise like synaptic plasticity and neurogenesis. In addition to known exerkines, they are loaded with other modulatory cargo such as microRNA (miRNA), an epigenetic regulator that regulates gene expression levels. How exercise-induced sEVs mediate exercise dependent improvements in MDD is unknown. Here, we perform a thorough survey of the current literature to elucidate the potential role of sEVs in the context of neurobiological changes seen with exercise and depression by summarizing studies on exercise and MDD, exercise and sEVs, and finally, sEVs as they relate to MDD. Moreover, we describe the links between peripheral sEV levels and their potential for infiltration into the brain. While literature suggests that aerobic exercise is protective against the development of mood disorders, there remains a scarcity of data on the therapeutic effects of exercise. Recent studies have shown that aerobic exercise does not appear to influence sEV size, but rather influence their concentration and cargo. These molecules have been independently implicated in numerous neuropsychiatric disorders. Taken together, these studies suggest that concentration of sEVs are increased post exercise, and they may contain specifically packaged protective cargo representing a novel therapeutic for MDD.

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Autophagy regulates the release of exercise factors and their beneficial effects on spatial memory recall

Cited by 5 publications

References 59 publications

Drug Repurposing of Metformin for the Treatment of Haloperidol-Related Behavior Disorders and Oxidative Stress: A Preliminary Study

Drug Repurposing of Metformin for the Treatment of Haloperidol-Related Behavior Disorders and Oxidative Stress: A Preliminary Study

Exercise-induced neuroplasticity: a new perspective on rehabilitation for chronic low back pain

Running from stress: a perspective on the potential benefits of exercise-induced small extracellular vesicles for individuals with major depressive disorder

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