Dataset Information

The effect of propofol on hypoxia- and TNF-α-mediated BDNF/TrkB pathway dysregulation in primary rat hippocampal neurons.

ABSTRACT:

Aims

Hypoxia and inflammation may lead to BDNF/TrkB dysregulation and neurological disorders. Propofol is an anesthetic with neuroprotective properties. We wondered whether and how propofol affected BDNF/TrkB pathway in hippocampal neurons and astrocytes.

Methods

Primary rat hippocampal neurons and astrocytes were cultured and exposed to propofol followed by hypoxia or TNF-α treatment. The expression of BDNF and the expression/truncation/phosphorylation of TrkB were measured. The underlying mechanisms were investigated.

Results

Hypoxia and TNF-α reduced the expression of BDNF, which was reversed by pretreatment of 25 μM propofol in hippocampal neurons. Furthermore, hypoxia and TNF-α increased the phosphorylation of ERK and phosphorylation of CREB at Ser142, while reduced the phosphorylation of CREB at Ser133, which were all reversed by 25 μM propofol and 10 μM ERK inhibitor. In addition, hypoxia or TNF-α did not affect TrkB expression, truncation, or phosphorylation in hippocampal neurons and astrocytes. However, in hippocampal neurons, 50 μM propofol induced TrkB phosphorylation, which may be mediated by p35 expression and Cdk5 activation, as suggested by the data showing that blockade of p35 or Cdk5 expression mitigated propofol-induced TrkB phosphorylation.

Conclusions

Propofol modulated BDNF/TrkB pathway in hippocampal neurons via ERK/CREB and p35/Cdk5 under the condition of hypoxia or TNF-α exposure.

SUBMITTER: Tao W

PROVIDER: S-EPMC8981449 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Publications

The effect of propofol on hypoxia- and TNF-α-mediated BDNF/TrkB pathway dysregulation in primary rat hippocampal neurons.

Tao Weiping W Zhang Xuesong X Ding Juan J Yu Shijian S Ge Peiqing P Han Jingfeng J Luo Xing X Cui Wei W Chen Jiawei J

CNS neuroscience & therapeutics 20220203 5

<h4>Aims</h4>Hypoxia and inflammation may lead to BDNF/TrkB dysregulation and neurological disorders. Propofol is an anesthetic with neuroprotective properties. We wondered whether and how propofol affected BDNF/TrkB pathway in hippocampal neurons and astrocytes.<h4>Methods</h4>Primary rat hippocampal neurons and astrocytes were cultured and exposed to propofol followed by hypoxia or TNF-α treatment. The expression of BDNF and the expression/truncation/phosphorylation of TrkB were measured. The ...[more]

PMID: 35112804

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Project description:Dysregulation of synaptic development and function has been implicated in the pathophysiology of neurodegenerative disorders and mental disease. A neurotrophin that has an important function in neuronal and synaptic development is brain-derived neurotrophic factor (BDNF). In this communication, we examined the effects of lead (Pb(2+)) exposure on BDNF-tropomyosin-related kinase B (TrkB) signaling during the period of synaptogenesis in cultured neurons derived from embryonic rat hippocampi. We show that Pb(2+) exposure decreases BDNF gene and protein expression, and it may also alter the transport of BDNF vesicles to sites of release by altering Huntingtin phosphorylation and protein levels. Combined, these effects of Pb(2+) resulted in decreased concentrations of extracellular mature BDNF. The effect of Pb(2+) on BDNF gene expression was associated with a specific decrease in calcium-sensitive exon IV transcript levels and reduced phosphorylation and protein expression of the transcriptional repressor methyl-CpG-binding protein (MeCP2). TrkB protein levels and autophosphorylation at tyrosine 816 were significantly decreased by Pb(2+) exposure with a concomitant increase in p75 neurotrophin receptor (p75(NTR)) levels and altered TrkB-p75(NTR) colocalization. Finally, phosphorylation of Synapsin I, a presynaptic target of BDNF-TrkB signaling, was significantly decreased by Pb(2+) exposure with no effect on total Synapsin I protein levels. This effect of Pb(2+) exposure on Synapsin I phosphorylation may help explain the impairment in vesicular release documented by us previously (Neal, A. P., Stansfield, K. H., Worley, P. F., Thompson, R. E., and Guilarte, T. R. (2010). Lead exposure during synaptogenesis alters vesicular proteins and impairs vesicular release: Potential role of N-Methyl-D-aspartate receptor (NMDAR) dependent BDNF signaling. Toxicol. Sci. 116, 249-263) because it controls vesicle movement from the reserve pool to the readily releasable pool. In summary, the present study demonstrates that Pb(2+) exposure during the period of synaptogenesis of hippocampal neurons in culture disrupts multiple synaptic processes regulated by BDNF-TrkB signaling with long-term consequences for synaptic function and neuronal development.

Project description:BackgroundPropofol is a commonly used general anesthetic that may cause neuronal damage, especially in infants and young children. Mitochondria play an essential role in cellular metabolism and signal transduction. Propofol may cause neurotoxicity by inhibiting mitochondrial function, but the mechanism by this which occurs remains unclear.MethodsFirst, the primary rat hippocampal neurons were cultured for 7 days in vitro. The neurons were incubated with propofol at different times or different concentrations, and then the adenosine triphosphate (ATP), reactive oxygen species (ROS), mitochondrial membrane potential, and apoptosis-related proteins were analyzed. Based on the results of the 1st phase, the neurons were then incubated with propofol (100 µM) or corresponding reagents, including 5-aminoimidazole-4-carboxamide ribonucleotide, tenovin-1, and pifithrin-α. Subsequently, the ATP, ROS, mitochondrial membrane potential, phospho-adenosine 5'-monophosphate-activated protein kinase (p-AMPK), protein 53 (p53), and related apoptosis proteins were analyzed.ResultsHigher propofol concentrations or longer incubation times were associated with more pronounced decreases in ATP, B-cell lymphoma 2 (Bcl-2), and mitochondrial membrane potential, and more pronounced increases in ROS, BCL2-associated X (Bax), Cytochrome C (CytC), and cleaved caspase-9. Additionally, after incubation with propofol (100 µM), neuronal Bcl-2, p-AMPK, ATP, and mitochondrial membrane potential were downregulated, and ROS, p53, CytC, Bax, cleaved caspase-3, and cleaved caspase-9 were upregulated. AMPK activators or p53 inhibitors reversed the above-mentioned changes.ConclusionsPropofol (100 µM)-induced mitochondrial damage in fetal rat hippocampal neurons may be mediated by the AMPK/p53 signaling pathway. Propofol (100 µM) was shown to inhibit the activity of AMPK in neurons, upregulate the expression of p53, and then activate the mitochondrial-dependent apoptosis pathway, which may lead to neuronal apoptosis.

Dataset Information

The effect of propofol on hypoxia- and TNF-α-mediated BDNF/TrkB pathway dysregulation in primary rat hippocampal neurons.

Aims

Methods

Results

Conclusions

Publications

The effect of propofol on hypoxia- and TNF-α-mediated BDNF/TrkB pathway dysregulation in primary rat hippocampal neurons.

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