Protective Effects of Melatonin on Neurogenesis Impairment in Neurological Disorders and Its Relevant Molecular Mechanisms

Leung, Joseph Wai-Hin; Cheung, Kwok-Kuen; Ngai, Shirley P.C.; Tsang, Hector W.H.; Lau, Benson Wui-Man

doi:10.3390/ijms21165645

Cited by 29 publications

(33 citation statements)

References 126 publications

(154 reference statements)

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“…Several of these function in development, morphology ( wnt4, wnt11f2, irx2a, msx2b , sox19a , tbx5a) [ 111 , 112 , 113 , 114 , 115 , 116 ] and cell proliferation (msx2b ) [ 117 ]. Other genes belonging to torpor_NET_only function in neurogenesis (Foxi1, irx2a, sox19a ) [ 118 , 119 ], neuron differentiation ( emx3, lmx1bb ) [ 120 , 121 ], synaptic function ( sncga ) [ 122 ] and plasticity ( pcp4a ) [ 123 , 124 ] which may be globally upregulated in response to the melatonin which has previously been associated with promoting neurogenesis [ 125 , 126 ]. Upregulation of stem cell, developmental and proliferative genes might offer protective affects by increasing cell survival and ensuring correct morphology during cell replacement responses, while those genes involved in neuronal development should be investigated further for signs of neuroprotective affects in situ .…”

Section: Resultsmentioning

confidence: 99%

Induced Torpor as a Countermeasure for Low Dose Radiation Exposure in a Zebrafish Model

Cahill

Silveira

Renaud

et al. 2021

Cells

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The development of the Artemis programme with the goal of returning to the moon is spurring technology advances that will eventually take humans to Mars and herald a new era of interplanetary space travel. However, long-term space travel poses unique challenges including exposure to ionising radiation from galactic cosmic rays and potential solar particle events, exposure to microgravity and specific nutritional challenges arising from earth independent exploration. Ionising radiation is one of the major obstacles facing future space travel as it can generate oxidative stress and directly damage cellular structures such as DNA, in turn causing genomic instability, telomere shortening, extracellular-matrix remodelling and persistent inflammation. In the gastrointestinal tract (GIT) this can lead to leaky gut syndrome, perforations and motility issues, which impact GIT functionality and affect nutritional status. While current countermeasures such as shielding from the spacecraft can attenuate harmful biological effects, they produce harmful secondary particles that contribute to radiation exposure. We hypothesised that induction of a torpor-like state would confer a radioprotective effect given the evidence that hibernation extends survival times in irradiated squirrels compared to active controls. To test this hypothesis, a torpor-like state was induced in zebrafish using melatonin treatment and reduced temperature, and radiation exposure was administered twice over the course of 10 days. The protective effects of induced-torpor were assessed via RNA sequencing and qPCR of mRNA extracted from the GIT. Pathway and network analysis were performed on the transcriptomic data to characterise the genomic signatures in radiation, torpor and torpor + radiation groups. Phenotypic analyses revealed that melatonin and reduced temperature successfully induced a torpor-like state in zebrafish as shown by decreased metabolism and activity levels. Genomic analyses indicated that low dose radiation caused DNA damage and oxidative stress triggering a stress response, including steroidal signalling and changes to metabolism, and cell cycle arrest. Torpor attenuated the stress response through an increase in pro-survival signals, reduced oxidative stress via the oxygen effect and detection and removal of misfolded proteins. This proof-of-concept model provides compelling initial evidence for utilizing an induced torpor-like state as a potential countermeasure for radiation exposure.

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Section: Resultsmentioning

confidence: 99%

Induced Torpor as a Countermeasure for Low Dose Radiation Exposure in a Zebrafish Model

Cahill

Silveira

Renaud

et al. 2021

Cells

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“…Second, as molecular mechanisms regarding the protective effects of melatonin in the collagenase-induced model remain poorly understood and melatonin possesses anti-microglial activation property, the effects of melatonin on different microglial-related inflammatory pathways can be investigated in this ICH model. Third, the role of melatonin in enhancing recovery after ICH via promoting endogenous neurogenesis can be explored in the collagenase-induced model because recent studies showed that melatonin protected against different neurological diseases by stimulation of endogenous neurogenesis (26).…”

Section: Discussionmentioning

confidence: 99%

“…Attributing to its direct antioxidant, anti-inflammatory, and anti-apoptotic properties, melatonin is a neuroprotective molecule against different neurological diseases (23)(24)(25). Recent studies have also uncovered its functions on neurogenesis promotion (26).…”

Section: Introductionmentioning

confidence: 99%

Melatonin attenuates microglial activation and improves neurological functions in rat model of collagenase-induced intracerebral hemorrhage

Leung¹,

Cheung²

2021

Melatonin Res.

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Intracerebral hemorrhage (ICH) is a severe form of stroke with a high mortality rate. It is also an important cause of permanent disability. Apart from hematoma growth and edema development, inflammatory responses and oxidative stress are responsible for poor outcomes after ICH. Due to its antioxidant, anti-inflammatory and anti-apoptotic properties, melatonin is a neuroprotective molecule against different neurological diseases. The protective roles of melatonin on ICH, particularly in the collagenase-induced ICH model, have not been well studied. The present study aims to explore neuroprotective effects of melatonin against ICH. At 24 hours after ICH induction, rats exhibited neurological deficits with mild loss in body weight (BW). Hematoma was found in the brain parenchyma with ED-1+ activated microglia and TUNEL+ apoptotic cells in the perihematomal region. As an in vitro model of ICH, SH-SY5Y cells were treated with red blood cell lysate. This treatment significantly reduced cell viability; however, melatonin (10-5 M) restored the cell viability. At 72 hours after ICH, rats treated with melatonin (50 mg/kg) at 2, 24 and 48 hours had reduced perihematomal microglial activation. However, there was no effect on hematoma size or perihematomal apoptosis. We further treated rats with 50 mg/kg melatonin starting at 2 hours and repeating at 24-hour intervals for two or seven more days. Both melatonin treatments improved post-ICH neurological functions, and the effect was most pronounced at 4 days after ICH. Since studies regarding the protective roles of melatonin on ICH remain very limited, our study advances our understanding of the potential use of melatonin as a treatment for ICH.

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“…Restoring rhythmicity via chronotherapy may ameliorate the symptoms of myriad neurological disorders that involve aberrant adult neurogenesis (Albrecht, 2017; Leung et al., 2020; McClung, 2013; Schnell, Albrecht, et al., 2014). In this regard, the circadian hormone melatonin appears to be a very promising therapeutic candidate for depression, Alzheimer's disease, neurodegenerative diseases and CNS injuries (Leung et al., 2020; Mihardja et al., 2020; Song, 2019; Valdes‐Tovar et al., 2018). In vitro, melatonin promoted survival of new neurons derived from hippocampal NSPCs, and increased survival of NSCPs and post‐mitotic immature neurons, which may explain its antidepressant effects in the Porsolt swim test (Ramirez‐Rodriguez et al., 2009).…”

Section: Circadian Control Of Stem Cell Behaviourmentioning

confidence: 99%

Regulation of tissue regeneration by the circadian clock

Ruby

Major

Hinrichsen

2021

Eur J of Neuroscience

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Circadian rhythms are regulated by a highly conserved transcriptional/translational feedback loop that maintains approximately 24‐hr periodicity from cellular to organismal levels. Much research effort is being devoted to understanding how the outputs of the master clock affect peripheral oscillators, and in turn, numerous biological processes. Recent studies have revealed roles for circadian timing in the regulation of numerous cellular behaviours in support of complex tissue regeneration. One such role involves the interaction between the circadian clockwork and the cell cycle. The molecular mechanisms that control the cell cycle create a system of regulation that allows for high fidelity DNA synthesis, mitosis and apoptosis. In recent years, it has become clear that clock gene products are required for proper DNA synthesis and cell cycle progression, and conversely, elements of the cell cycle cascade feedback to influence molecular circadian timing mechanisms. It is through this crosstalk that the circadian system orchestrates stem cell proliferation, niche exit and control of the signalling pathways that govern differentiation and self‐renewal. In this review, we discuss the evidence for circadian control of tissue homeostasis and repair and suggest new avenues for research.

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Protective Effects of Melatonin on Neurogenesis Impairment in Neurological Disorders and Its Relevant Molecular Mechanisms

Cited by 29 publications

References 126 publications

Induced Torpor as a Countermeasure for Low Dose Radiation Exposure in a Zebrafish Model

Induced Torpor as a Countermeasure for Low Dose Radiation Exposure in a Zebrafish Model

Melatonin attenuates microglial activation and improves neurological functions in rat model of collagenase-induced intracerebral hemorrhage

Regulation of tissue regeneration by the circadian clock

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