Melatonin regulates the autophagic flux via activation of alpha‐7 nicotinic acetylcholine receptors

Jeong, Jae‐Kyo; Park, Sang-Youel

doi:10.1111/jpi.12235

Cited by 41 publications

(28 citation statements)

References 69 publications

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“…Moreover, in a previous study of our group, we showed that the neuroprotective effect of melatonin against ischemia was partially mediated by alpha‐7 nicotinic receptor (α7nAchR) modulation . Related to that, Jeong et al described that melatonin regulates the autophagic flux via activation of α7nAchR, playing a pivotal role in neuroprotection of prion‐mediated mitochondrial neurotoxicity. Thus, melatonin could also be acting through α7nAchR signaling pathway to restore the autophagic flux blockade displayed by tau protein.…”

Section: Discussionmentioning

confidence: 78%

Pharmacological doses of melatonin impede cognitive decline in tau‐related Alzheimer models, once tauopathy is initiated, by restoring the autophagic flux

Luengo¹,

Buendía

Fernández‐Mendívil³

et al. 2019

Journal of Pineal Research

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Alterations in autophagy are increasingly being recognized in the pathogenesis of proteinopathies like Alzheimer's disease (AD). This study was conducted to evaluate whether melatonin treatment could provide beneficial effects in an Alzheimer model related to tauopathy by improving the autophagic flux and, thereby, prevent cognitive decline. The injection of AAV‐hTauP301L viral vectors and treatment/injection with okadaic acid were used to achieve mouse and human ex vivo, and in vivo tau‐related models. Melatonin (10 μmol/L) impeded oxidative stress, tau hyperphosphorylation, and cell death by restoring autophagy flux in the ex vivo models. In the in vivo studies, intracerebroventricular injection of AAV‐hTauP301L increased oxidative stress, neuroinflammation, and tau hyperphosphorylation in the hippocampus 7 days after the injection, without inducing cognitive impairment; however, when animals were maintained for 28 days, cognitive decline was apparent. Interestingly, late melatonin treatment (10 mg/kg), starting once the alterations mentioned above were established (from day 7 to day 28), reduced oxidative stress, neuroinflammation, tau hyperphosphorylation, and caspase‐3 activation; these observations correlated with restoration of the autophagy flux and memory improvement. This study highlights the importance of autophagic dysregulation in tauopathy and how administration of pharmacological doses of melatonin, once tauopathy is initiated, can restore the autophagy flux, reduce proteinopathy, and prevent cognitive decline. We therefore propose exogenous melatonin supplementation or the development of melatonin derivatives to improve autophagy flux for the treatment of proteinopathies like AD.

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Section: Discussionmentioning

confidence: 78%

Pharmacological doses of melatonin impede cognitive decline in tau‐related Alzheimer models, once tauopathy is initiated, by restoring the autophagic flux

Luengo¹,

Buendía

Fernández‐Mendívil³

et al. 2019

Journal of Pineal Research

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“…The association between activating α7nAChR and induction of autophagy in neurons has been demonstrated. Jeong and Park reported that melatonin, a secretory hormone produced from various organs, enhanced the activation of autophagy process in neurons through the upregulation of α7nAChR signaling pathway, thus playing an important role in neuroprotection in prion-mediated neurodegenerative diseases (45). In their other article, the authors showed that the activation of α7nAChR stimulated by cellular prion protein expression contributed to the induction of autophagy flux in neurons, which played a pivotal role in neuroprotection (46).…”

Section: Discussionmentioning

confidence: 99%

Autophagy Plays an Important Role in Anti-inflammatory Mechanisms Stimulated by Alpha7 Nicotinic Acetylcholine Receptor

Shao

Peng

et al. 2017

Front. Immunol.

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Alpha7 nicotinic acetylcholine receptor (α7nAChR) has been reported to alleviate neuroinflammation. Here, we aimed to determine the role of autophagy in α7nAChR-mediated inhibition of neuroinflammation and its underlying mechanism. Experimental autoimmune encephalomyelitis (EAE) mice and lipopolysaccharide-stimulated BV2 microglia were used as in vivo and in vitro models of neuroinflammation, respectively. The severity of EAE was evaluated with neurological scoring. Autophagy-related proteins (Beclin 1, LC3-II/I, p62/SQSTM1) were detected by immunoblot. Autophagosomes were observed using transmission electron microscopy and tandem fluorescent mRFP-GFP-LC3 plasmid was applied to test autophagy flux. The mRNA levels of interleukin-6 (IL-6), IL-1β, IL-18, and tumor necrosis factor-α (TNF-α) were detected by real-time PCR. We used 3-methyladenine (3-MA) and autophagy-related gene 5 small interfering RNA (Atg5 siRNA) to block autophagy in vivo and in vitro, respectively. Activating α7nAChR with PNU282987 ameliorates EAE severity and spinal inflammatory infiltration in EAE mice. PNU282987 treatment also enhanced monocyte/microglia autophagy (Beclin 1, LC3-II/I ratio, p62/SQSTM1, colocalization of CD45- or CD68-positive cells with LC3) both in spinal cord and spleen from EAE mice. The beneficial effects of PNU282987 on EAE mice were partly abolished by 3-MA, an autophagy inhibitor. In vitro, PNU282987 treatment increased autophagy and promoted autophagy flux. Blockade of autophagy by Atg5 siRNA or bafilomycin A1 attenuated the inhibitory effect of PNU282987 on IL-6, IL-1β, IL-18, and TNF-α mRNA. Our results demonstrate for the first time that activating α7nAChR enhances monocyte/microglia autophagy, which suppresses neuroinflammation and thus plays an alleviative role in EAE.

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“…Deleterious effects triggered by endogenous molecules or by dysfunctional processes are the basis of neurodegenerative diseases and brain tumors. Inflammatory changes, ROS and RNS formation, mitochondrial dysfunction, excitotoxicity, apoptosis, and protein aggregation are processes commonly found in these cases and related to neuron injuries [54]. …”

Section: Melatoninergic System and Neuroprotectionmentioning

confidence: 99%

“…Another interesting link between melatoninergic system and brain inflammatory responses is the regulation of the alpha-7-nicotinic acetylcholine receptors ( α 7nAchR) by melatonin [54, 67–69]. Cholinergic control of inflammation adjusts the intensity of appropriate immune responses and α 7nAchR activation in immunocompetent cells shifts the immune responses towards a more anti-inflammatory profile.…”

Section: Melatoninergic System and Neuroprotectionmentioning

confidence: 99%

“…Therefore, melatonin improves α 7nAchR-dependent cholinergic activities. Indeed, melatonin protects neurons from prion-mediated mitochondrial neurotoxicity by increasing the α 7nAchR-mediated autophagic flux [54] and ischemic neurons survival by increasing the heme oxygenase-1 (HO-1) expression [69]. Furthermore, melatonin ameliorates cholinergic dysfunction and avoids neuronal apoptosis in the APP 695 transgenic mouse model of AD [67].…”

Section: Melatoninergic System and Neuroprotectionmentioning

confidence: 99%

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Melatoninergic System in Parkinson’s Disease: From Neuroprotection to the Management of Motor and Nonmotor Symptoms

Mack

Schamne

Sampaio

et al. 2016

Oxidative Medicine and Cellular Longevity

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Melatonin is synthesized by several tissues besides the pineal gland, and beyond its regulatory effects in light-dark cycle, melatonin is a hormone with neuroprotective, anti-inflammatory, and antioxidant properties. Melatonin acts as a free-radical scavenger, reducing reactive species and improving mitochondrial homeostasis. Melatonin also regulates the expression of neurotrophins that are involved in the survival of dopaminergic neurons and reduces α-synuclein aggregation, thus protecting the dopaminergic system against damage. The unbalance of pineal melatonin synthesis can predispose the organism to inflammatory and neurodegenerative diseases such as Parkinson's disease (PD). The aim of this review is to summarize the knowledge about the potential role of the melatoninergic system in the pathogenesis and treatment of PD. The literature reviewed here indicates that PD is associated with impaired brain expression of melatonin and its receptors MT1 and MT2. Exogenous melatonin treatment presented an outstanding neuroprotective effect in animal models of PD induced by different toxins, such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, paraquat, and maneb. Despite the neuroprotective effects and the improvement of motor impairments, melatonin also presents the potential to improve nonmotor symptoms commonly experienced by PD patients such as sleep and anxiety disorders, depression, and memory dysfunction.

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Melatonin regulates the autophagic flux via activation of alpha‐7 nicotinic acetylcholine receptors

Cited by 41 publications

References 69 publications

Pharmacological doses of melatonin impede cognitive decline in tau‐related Alzheimer models, once tauopathy is initiated, by restoring the autophagic flux

Pharmacological doses of melatonin impede cognitive decline in tau‐related Alzheimer models, once tauopathy is initiated, by restoring the autophagic flux

Autophagy Plays an Important Role in Anti-inflammatory Mechanisms Stimulated by Alpha7 Nicotinic Acetylcholine Receptor

Melatoninergic System in Parkinson’s Disease: From Neuroprotection to the Management of Motor and Nonmotor Symptoms

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