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Front. Mol. Neurosci. | doi: 10.3389/fnmol.2019.00248

Intra-CA1 administration of minocycline alters the expression of inflammation-related genes in hippocampus of CCI rats

 Wei J. Zeng1*, Li He1, Rui XU1, Na j. Yang1 and Tao Xu1
  • 1Zunyi Medical University, China

Neuropathic pain is a complex, chronic pain state that is usually caused by peripheral nerve injury in a large number of patients. Recent reports suggest that the inflammation-related cytokines accumulation in dorsal root ganglion, dorsal spinal cord, hippocampus, thalamus and somatosensoric cortex are paralleled by pain behavior in different animal models of neuropathic pain (Al-Amin et al., 2011; Sun et al., 2016; Liu et al., 2017; Chang et al., 2018). In the chronic constriction injury (CCI) and the spared nerve injury models of neuropathic pain rats, an increase in interleukin 1 beta (IL-1β), interleukin 6 (IL-6), nerve growth factor (NGF) and glial cell-derived neurotrophic factor (GDNF) were observed in most brain regions (Al-Amin et al., 2011). The overproduction of tumor necrosis factor-α (TNF-α) may regulate synaptic plasticity in rat hippocampus through microglia-dependent mechanism after spared nerve injury of the sciatic nerve (Liu et al., 2017). However, it is not clear whether other inflammation-related neuroactive substances will be affected after microglia activation in rat hippocampus after peripheral nerve injury.
  It is clear that many kinds of toll-like receptors (TLRs) are expressed in hippocampus and act as a type of pattern-recognition receptor that promote innate immune defense. TLR1 expression in hippocampus was increased in the neurons, microglia, and astrocytes in a kainic acid-induced seizure mouse model (Wang et al., 2015). TLR (2, 3, 4, 7 and 9) genes were significantly up-regulated in hippocampus of rats exposed to restraint stress (Timberlake et al., 2018). TLR2 and TLR4 in rat hippocampus are involved in lipopolysaccharide (LPS)-induced neuron cell death (He et al., 2013; Henry et al., 2014). TLR3-induced the increased expression of IL-1β in rat hippocampus was also observed by Henry et al (Henry et al., 2014). TLR8, expressed in most regions of the brain and localizes mainly to neuronal somata, is involved in injury and neurite outgrowth associated with neural development (Ma et al., 2006). It is well known that TLRs activation is often associated with the production and release of inflammatory cytokines in many different types of cells. Despite these observational findings, it is not known the relationship between the changes of TLRs expression and microglia activation in hippocampus of CCI rats.  
  Previous studies reveal that chemokine production is enhanced in various neurodegenerative and neuroimmunological diseases often accompanied by neuropathic pain (Cartier et al., 2005). CXCL13 is highly upregulated in spinal neurons after spinal nerve ligation and induces spinal astrocyte activation via receptor CXCR5 (Zhang et al., 2017). Chemokine C-C motif ligand 2 (CCL2, commonly known as monocyte chemoattractant protein-1, MCP-1) signaling in the rostral ventromedial medulla is involved in descending pain facilitation in rats with L5 spinal nerve ligation (SNL) (Guo et al., 2012). Chemokines CCL2 and CCL3 were induced in the thalamus and hippocampus, especially in the chronic time course after severe spinal cord injuries (Knerlich et al., 2011). The increased expression of IL-1β and CCL2 was found in hippocampus of CCI rats (Fiore et al., 2018). In addition, it was reported that CCL5 mRNA was found in 73.2% of neurons and in ~20% in glial cells in rat hippocampus (Lanfranco et al., 2018). However, no evidence directly addresses the relationship between microglia activation and chemokine accumulation in neuropathic hypersensitivity.
  There is a wealth of evidence to suggest that minocycline is a strong modulator of the neuroimmune response and readily permeates the blood–brain barrier (Stolp et al., 2007; Vonder et al., 2014). Clinically, minocycline is available as a parenteral formulation and can be administered by the intravenous route in patients with traumatic brain injury resulting in immediate targeted concentrations (Rojewska et al., 2014). More recent evidence suggest that minocycline is effective at reducing allodynia in animal models of neuropathic pain, and that means it appears to be a promising drug that could be used in analgesia (Rojewska et al., 2014; LeBlanc et al., 2011). In the present study, minocycline is used to identify what inflammation-related genes at hippocampus are closely related to the increased microglia activity in CCI-induced neuropathic pain rats.
MATERIALS AND METHODS
Experimental Animals
The adult male Sprague-Dawley (SD) rats (200-220 g) were used in the present study. All animals were housed in a standard 12-h light/dark cycle. The protocol was prepared from SD rats in accordance with the National Institutes of Health guidelines in a manner that minimized animal suffering and animal numbers. All experiments were carried out in accordance with China animal welfare legislation and were approved by the Zunyi Medical University Committee on Ethics in the Care and Use of Laboratory Animals.

Keywords: neuropathic pain, Hippocampus, Microglia, Toll like receptor;, Chemokines

Received: 18 Oct 2018; Accepted: 26 Sep 2019.

Copyright: © 2019 Zeng, He, XU, Yang and Xu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Wei J. Zeng, Zunyi Medical University, Zunyi, China, junweizeng@sohu.com