Orthopedic surgery modulates neuropeptides and BDNF expression at the spinal and hippocampal levels

Zhang, Mingdong; Barde, Swapnali; Yang, Ting; Lei, Beilei; Eriksson, Lars; Mathew, Joseph P.; Andreska, Thomas; Akassoglou, Katerina; Harkany, Tibor; Hökfelt, Tomas; Terrando, Niccolò

doi:10.1073/pnas.1614017113

Cited by 61 publications

(66 citation statements)

References 137 publications

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“…Bone fracture such as tibia facture results in persistent postoperative pain as well as microglial activation in the spinal cord (Wei et al, 2016; Zhang et al, 2016a). We evaluated the effects of p38α and p38β MAPK ASO (300 µg, intrathecal) on male mice in a tibia fracture model.…”

Section: Resultsmentioning

confidence: 99%

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Intrathecal administration of antisense oligonucleotide against p38α but not p38β MAP kinase isoform reduces neuropathic and postoperative pain and TLR4-induced pain in male mice

Luo

Fitzsimmons

Mohan

et al. 2018

Brain, Behavior, and Immunity

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p38 mitogen-activated protein kinase (MAPK) consists of two major isoforms: p38α and p38β; however, it remains unclear which isoform is more important for chronic pain development. Recently, we developed potent, long-lasting, and p38 MAPK subtype-specific antisense oligonucleotides (ASOs). We examined the therapeutic effects of isoform-specific ASOs in several chronic pain models following single intrathecal injection (300 µg/10 µl) in CD1 mice. In the chronic constriction injury (CCI) model, p38α MAPK ASO, given on post-operative day 5, reduced CCI-induced mechanical allodynia in male but not female mice. In contrast, mechanical allodynia after CCI in both sexes was not affected by p38β MAPK ASO. Intrathecal injection of p38α or p38β ASO resulted in a partial reduction (≈50%) of spinal p38α or p38β mRNA level, respectively, in both sexes at two weeks. In contrast, intrathecal injection of the ASOs did not affect p38α and p38β MAPK mRNA levels in dorsal root ganglia. Intrathecal p38α ASO also reduced postoperative pain (mechanical and cold allodynia) in male mice after tibia fracture. However, intrathecal p38α ASO had no effect on mechanical allodynia in male mice after paclitaxel treatment. Intrathecal p38α MAPK ASO pre-treatment also prevented TLR4-mediated mechanical allodynia and downregulated levels of p38α MAPK and phosphorylated p38 MAPK following intrathecal treatment of lipopolysaccharide. In summary, our findings suggest that p38α MAPK is the major p38 MAPK isoform in the spinal cord and regulates chronic pain in a sex and model-dependent manner. Intrathecal p38α MAPK ASO may offer a new treatment for some chronic pain conditions.

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Section: Resultsmentioning

confidence: 99%

“…It is possible that the onset of neuropathic pain could be slower with silk suture. Tibial facture (TF) was performed under isoflurane anesthesia (Zhang et al, 2016b). Muscles were disassociated following an incision on the left hindpaw.…”

Section: Methodsmentioning

confidence: 99%

Intrathecal administration of antisense oligonucleotide against p38α but not p38β MAP kinase isoform reduces neuropathic and postoperative pain and TLR4-induced pain in male mice

Luo

Fitzsimmons

Mohan

et al. 2018

Brain, Behavior, and Immunity

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“…using siRNAs) (Bayerl et al, 2016;Lin et al, 2016). These approaches can provide a range of information from a general understanding of the physiological function of a neuropeptide to judging whether neuropeptides are therapeutically active (Wickström et al, 2004;Zhang et al, 2016). Neuropeptides, their antagonists and siRNAs can be delivered to an organism in several different ways, including by injection (Javadian et al, 2016;Narváez et al, 2016), incubation in media containing molecules (Chen et al, 2016b;Kasica et al, 2016) and even microdialysis (Torregrossa and Kalivas, 2008).…”

Section: Altering Neuropeptide Contentmentioning

confidence: 99%

New techniques, applications and perspectives in neuropeptide research

DeLaney

Buchberger

Atkinson

et al. 2018

Journal of Experimental Biology

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Neuropeptides are one of the most diverse classes of signaling molecules and have attracted great interest over the years owing to their roles in regulation of a wide range of physiological processes. However, there are unique challenges associated with neuropeptide studies stemming from the highly variable molecular sizes of the peptides, low concentrations, high degree of structural diversity and large number of isoforms. As a result, much effort has been focused on developing new techniques for studying neuropeptides, as well as novel applications directed towards learning more about these endogenous peptides. The areas of importance for neuropeptide studies include structure, localization within tissues, interaction with their receptors, including ion channels, and physiological function. Here, we discuss these aspects and the associated techniques, focusing on technologies that have demonstrated potential in advancing the field in recent years. Most identification and structural information has been gained by mass spectrometry, either alone or with confirmations from other techniques, such as nuclear magnetic resonance spectroscopy and other spectroscopic tools. While mass spectrometry and bioinformatic tools have proven to be the most powerful for large-scale analyses, they still rely heavily on complementary methods for confirmation. Localization within tissues, for example, can be probed by mass spectrometry imaging, immunohistochemistry and radioimmunoassays. Functional information has been gained primarily from behavioral studies coupled with tissue-specific assays, electrophysiology, mass spectrometry and optogenetic tools. Concerning the receptors for neuropeptides, the discovery of ion channels that are directly gated by neuropeptides opens up the possibility of developing a new generation of tools for neuroscience, which could be used to monitor neuropeptide release or to specifically change the membrane potential of neurons. It is expected that future neuropeptide research will involve the integration of complementary bioanalytical technologies and functional assays.

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“…Investigating the role of mediators of systemic and neuroinflammation has become one of the cornerstones of POD and POCD research (41). Animal models brought about exciting results including upregulation of several inflammatory pathways and decreased neuronal plasticity in hippocampal regions while cortical regions were generally spared, which is in line with cognitive deficits observed in humans (12,13,33,93,94). This motivated studies in humans that assessed the association of markers of inflammation with POD and POCD, yet findings were ambiguous.…”

Section: Role Of Inflammatory Pathwaysmentioning

confidence: 99%

Evaluating mechanisms of postoperative delirium and cognitive dysfunction following elective spine surgery in elderly patients (CONFESS): study protocol for a prospective observational trial

Müller

Nowak

Dewey

et al. 2018

Preprint

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Background Elderly people are a rapidly growing proportion of the world's population that increasingly undergo major elective spine surgery. They are yet at particular high risk for postoperative delirium (POD), which is associated with longer hospital stays, higher costs, risk for delayed complications, long-term care dependency and cognitive dysfunction (POCD). It is insufficiently understood, which mechanisms and, particularly modifiable, risk factors contribute to the development of POD and POCD following these major but plannable surgeries. A better understanding thereof would help to adapt medical management and surgical strategies to individual risk profiles. Methods This is a single-center observational study that is jointly conducted by the departments of Neurosurgery, Neurology and Anesthesiology at a tertiary care hospital in Germany. All patients presenting to the neurosurgery outpatient clinic or ward for elective spine surgery are screened for eligibility. Inclusion criteria are age ≥ 60 years, indication for elective spine surgery, ability to give informed consent without assistance and speaking German natively. Exclusion criteria include presence of neurodegenerative disease, diagnosis of any psychiatric disease, medication with central nervous system activity (e.g. antidepressants, antipsychotics, sedatives), impossibility to participate in follow-up, participation in an interventional trial, presence of electronic or displaceable metallic implants and active neoplasm. All patients are evaluated for their preoperative cognitive abilities and physical, mental and social health and wellbeing. They additionally receive preoperative cerebrovascular ultrasound and structural and functional brain imaging. The immediate postoperative period includes screening for POD and the investigation of markers of (neuro‑)inflammation. Preoperative examinations are repeated three months postoperatively to investigate the presence of POCD and its mechanisms. Discussion This is the first study to prospectively evaluate risk factors for POD and POCD in spine surgery including comprehensive pre- and postoperative assessments of cognitive abilities, markers of (neuro‑)inflammation, cerebral vasculature and structural and functional neuroimaging. The identification of, possibly common, mechanisms underlying POD and POCD would be a major step towards the definition of effective interventional strategies early in or even before the postoperative period, including the adaptation of surgical strategies to individual risk profiles.

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Orthopedic surgery modulates neuropeptides and BDNF expression at the spinal and hippocampal levels

Cited by 61 publications

References 137 publications

Intrathecal administration of antisense oligonucleotide against p38α but not p38β MAP kinase isoform reduces neuropathic and postoperative pain and TLR4-induced pain in male mice

Intrathecal administration of antisense oligonucleotide against p38α but not p38β MAP kinase isoform reduces neuropathic and postoperative pain and TLR4-induced pain in male mice

New techniques, applications and perspectives in neuropeptide research

Evaluating mechanisms of postoperative delirium and cognitive dysfunction following elective spine surgery in elderly patients (CONFESS): study protocol for a prospective observational trial

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