Effects of chronic manganese exposure on the learning and memory of rats by observing the changes in the hippocampal cAMP signaling pathway

Liang, Guiqiang; H, Qin; Zhang, Lie; Ma, Shuyan; Huang, Xiaowei; Lv, Yingnan; Li, Qing; Li, Qin; Xiong, Yi; Huang, Yifei; Chen, Kangcheng; Huang, Yuman; Shen, Yongchun; Nong, Jie; Yang, Xiaobo; Zou, Yue

doi:10.1016/j.fct.2015.07.005

Cited by 45 publications

(27 citation statements)

References 38 publications

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“…In 12 weeks at doses 10 and 20 mg/kg. In 18 weeks at doses 5, 10 and 20 mg/kg[163]Male Sprague-Dawley rats (6 weeks of age)Intraperitoneal injections 15 mg/kg MnCl 2 daily for 8 weeks.MWMThe escape latency in the Morris water maze test was significantly longer in the rats injected with Mn indicating worsening in spatial memory[164]Sprague-Dawley rats, 3-week- oldIntraperitoneal injections (5, 10, 20 mg/kg MnSO 4 ) 5 days a week for 24 weeksMWMMn exposure decreased the spatial learning ability in a dose- and time- dependent manner[169]Male Wistar ratsExposed intraperitoneally to MnCl 2 at doses 5, 10 or 20 mg/kg/day from PND 8–12Object and social recognition tasksPND 60–65: Rats exposed to the highest Mn dose failed to recognize a familiar object when replaced by a novel object as well as to recognize a familiar juvenile rat after a short period of time, indicating cognitive impairment[139]Adult male M. fascicularis macaques, 5 to 6 years oldMn was administered as MnSO 4 for 15 mg/kg/week for 5 weeks and then 20 mg /kg/week for the remainder of the study period (12 months)SOSS and5-CSRT tasksDeficits in performance of the SOSS task began to appear by the fourth month of Mn exposure but only became consistently significantly impaired beginning at the ninth month of Mn exposure. Performance on the 5-CSRT became significantly affected by the third month of Mn exposure[167]Adult male M. fascicularis monkeys with 5 to 6 years oldMnSO 4 at doses 10–15 mg/kg/week over an exposure periodlasting 272 ± 17 daysVariable delayed response taskAnimals developed subtle deficits in spatial working memory and had modest decreases in spontaneous activity and manual dexterity[166]Adult male M. fascicularis macaques, 5 to 6 years oldMnSO 4 at doses 15–20 mg/kg/week over an exposure period lasting 227.5 ± 17.3 daysVariable delayed response taskAnimals developed mild deficits in spatial working memory, more significant deficits in non-spatial working memory and no deficits in reference memory[165]

Abbreviations : 5-CSRT five choice serial reaction time, DA dopamine, MWM Morris water maze, PND post-natal day, SOSS self-ordered spatial search

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Section: Main Textmentioning

confidence: 99%

“Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies”

Peres

Schettinger

Chen

et al. 2016

BMC Pharmacol Toxicol

280

183

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Manganese (Mn) is an essential heavy metal. However, Mn’s nutritional aspects are paralleled by its role as a neurotoxicant upon excessive exposure. In this review, we covered recent advances in identifying mechanisms of Mn uptake and its molecular actions in the brain as well as promising neuroprotective strategies. The authors focused on reporting findings regarding Mn transport mechanisms, Mn effects on cholinergic system, behavioral alterations induced by Mn exposure and studies of neuroprotective strategies against Mn intoxication. We report that exposure to Mn may arise from environmental sources, occupational settings, food, total parenteral nutrition (TPN), methcathinone drug abuse or even genetic factors, such as mutation in the transporter SLC30A10. Accumulation of Mn occurs mainly in the basal ganglia and leads to a syndrome called manganism, whose symptoms of cognitive dysfunction and motor impairment resemble Parkinson’s disease (PD). Various neurotransmitter systems may be impaired due to Mn, especially dopaminergic, but also cholinergic and GABAergic. Several proteins have been identified to transport Mn, including divalent metal tranporter-1 (DMT-1), SLC30A10, transferrin and ferroportin and allow its accumulation in the central nervous system. Parallel to identification of Mn neurotoxic properties, neuroprotective strategies have been reported, and these include endogenous antioxidants (for instance, vitamin E), plant extracts (complex mixtures containing polyphenols and non-characterized components), iron chelating agents, precursors of glutathione (GSH), and synthetic compounds that can experimentally afford protection against Mn-induced neurotoxicity.

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Abbreviations : 5-CSRT five choice serial reaction time, DA dopamine, MWM Morris water maze, PND post-natal day, SOSS self-ordered spatial search

…”

Section: Main Textmentioning

confidence: 99%

“Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies”

Peres

Schettinger

Chen

et al. 2016

BMC Pharmacol Toxicol

280

183

View full text Add to dashboard Cite

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“…Several mechanisms for this have been proposed, including the regulation by γ‐aminobutyric acid‐B receptor, regulation of transcription factor myocyte‐enhancer factor 2, activation downstream of NF‐kB signaling pathway and related proinflammatory cytokines, increased downstream of proapoptotic proteins (Bcl‐2 family and caspase) expression, and reduction of BDNF expression . Our previous results showed that Mn exposure‐impaired cognitive abilities may be associated with decreased plasma BDNF levels in Mn‐exposed workers, and probably by inhibiting the hippocampal cAMP signaling pathway and BDNF in rats . However, the precise mechanism of Mn‐induced cognitive impairment remains unclear.…”

Section: Discussionmentioning

confidence: 97%

“…In addition, the pCREB can also regulate the expression of downstream apoptosis‐associated proteins, including Bcl‐2, Bax, caspase‐3, caspase‐8, and brain‐derived neurotrophic factor (BDNF), which have been found to promote the apoptosis of neurons, and share an association with aggravating cognitive dysfunction . Our previous studies showed that Mn exposure impaired hippocampus‐dependent cognitive function and reduced cAMP signaling and the protein levels of BDNF in occupational Mn‐exposed workers and chronic Mn‐treated rats . Nevertheless, the precise mechanism through the cAMP signaling pathway in Mn‐induced neurotoxicity is still not completely understood.…”

Section: Introductionmentioning

confidence: 99%

Pivotal role of cAMP‐PKA‐CREB signaling pathway in manganese‐induced neurotoxicity in PC12 cells

Yang

Ma²,

Wei

et al. 2019

Environmental Toxicology

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Manganese (Mn) plays a critical role in individual growth and development, yet excessive exposure can result in neurotoxicity, especially cognitive impairment. Neuronal apoptosis is considered as one of the mechanisms of Mn‐induced neurotoxicity. Recent evidence suggests that cAMP‐PKA‐CREB signaling regulates apoptosis and is associated with cognitive function. However, whether this pathway participates in Mn‐induced neurotoxicity is not completely understood. To fill this gap, in vitro cultures of PC12 cells were exposed to 0, 400, 500, and 600 μmol/L Mn for 24 hours, respectively. Another group of cells were pretreated with 10.0 μmol/L rolipram (a phosphodiesterase‐4 [PDE4] inhibitor) for 1 hour followed by 500 μmol/L Mn exposure for 24 hours. Flow cytometry, immunofluorescence staining, enzyme‐linked immunosorbent assay, and Western blot analysis were used to detect the apoptosis rate, protein levels of PDE4, cAMP signaling, and apoptosis‐associated proteins, respectively. We found that Mn exposure significantly inhibited cAMP signaling and protein expression of Bcl‐2, while increasing apoptosis rate, protein levels of PDE4, Bax, activated caspase‐3, and activated caspase‐8 in PC12 cells. Pretreatment of rolipram ameliorated Mn‐induced deficits in cAMP signaling and apoptosis. These findings demonstrate that cAMP‐PKA‐CREB signaling pathway‐induced apoptosis is involved in Mn‐induced neurotoxicity.

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“…Mn not only leads to manganism, which is a form of Parkinsonism, but it is also proposed to play a crucial role in PD etiology [80]. Multiple mechanisms are involved in Mn-induced neurotoxicity, including autophagy [55], oxidative stress[44], altered cAMP signaling [91], reactive oxygen species (ROS) generation [95], mitochondrial dysfunction [44], altered iron homeostasis [81] and altered acetylcholinesterase (AChE) activity [146]. Mn exposure induces α-Syn aggregation in non-human primates, and may also play a role in α-Syn protein fibrillation and oligomerization [138].…”

Section: Metalsmentioning

confidence: 99%

Role of neurotoxicants and traumatic brain injury in α-synuclein protein misfolding and aggregation

Rokad

Ghaisas

Harischandra

et al. 2017

Brain Research Bulletin

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Protein misfolding and aggregation are key pathological features of many neurodegenerative diseases including Parkinson’s disease (PD) and other forms of human Parkinsonism. PD is a complex and multifaceted disorder whose etiology is not fully understood. However, several lines of evidence support the multiple hit hypothesis that genetic vulnerability and environmental toxicants converge to trigger PD pathology. Alpha-synuclein (α-Syn) aggregation in the brain is an important pathophysiological characteristic of synucleinopathies including PD. Epidemiological and experimental studies have shown that metals and pesticides play a crucial role in α-Syn aggregation leading to the onset of various neurodegenerative diseases including PD. In this review, we will emphasize key findings of several epidemiological as well as experimental studies of metal- and pesticide-induced α-Syn aggregation and neurodegeneration. We will also discuss other factors such as traumatic brain injury and oxidative insult in the context of α-Syn-related neurodegenerative processes.

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Effects of chronic manganese exposure on the learning and memory of rats by observing the changes in the hippocampal cAMP signaling pathway

Cited by 45 publications

References 38 publications

“Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies”

“Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies”

Pivotal role of cAMP‐PKA‐CREB signaling pathway in manganese‐induced neurotoxicity in PC12 cells

Role of neurotoxicants and traumatic brain injury in α-synuclein protein misfolding and aggregation

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