Electric stimulation of the vagus nerve reduced mouse neuroinflammation induced by lipopolysaccharide

Abstract

BackgroundNeuroinflammation (NI) is a key feature in the pathogenesis and progression of infectious and non-infectious neuropathologies, and its amelioration usually improves the patient outcome. Peripheral inflammation may promote NI through microglia and astrocytes activation, an increased expression of inflammatory mediators and vascular permeability that may lead to neurodegeneration. Several anti-inflammatory strategies have been proposed to control peripheral inflammation. Among them, electrical stimulation of the vagus nerve (VNS) recently emerged as an alternative to effectively attenuate peripheral inflammation in a variety of pathological conditions with few side effects.Considering that NI underlies several neurologic pathologies we explored herein the possibility that electrically VNS can also exert anti-inflammatory effects in the brain.MethodsNI was experimentally induced by intraperitoneal injection of bacterial lipopolysaccharide (LPS) in C57BL/6 male mice; VNS with constant voltage (5 Hz, 0.75 mA, 2 ms) was applied for 30 s, 48 or 72 h after lipopolysaccharide injection. Twenty four hours later, pro-inflammatory cytokines (IL-1β, IL-6, TNFα) levels were measured by ELISA in brain and spleen extracts and total brain cells were isolated and microglia and macrophage proliferation and activation was assessed by flow cytometry. The level of ionized calcium binding adaptor molecule (Iba-1) and glial fibrillary acidic protein (GFAP) were estimated in whole brain extracts and in histologic slides by Western blot and immunohistochemistry, respectively.ResultsVNS significantly reduced the central levels of pro-inflammatory cytokines and the percentage of microglia (CD11b/CD45low) and macrophages (CD11b/CD45high), 24 h after the electrical stimulus in LPS stimulated mice. A significantly reduced level of Iba-1 expression was also observed in whole brain extracts and in the hippocampus, suggesting a reduction in activated microglia.ConclusionsVNS is a feasible therapeutic tool to attenuate the NI reaction. Considering that NI accompanies different neuropathologies VNS is a relevant alternative to modulate NI, of particular interest for chronic neurological diseases.

Modulation of neuroinflammation and memory dysfunction using percutaneous vagus nerve stimulation in mice

“…In our study pVNS improved microglial morphology after LPS injection, with more cells retaining ramified branches as found under homeostatic states. As anticipated, pVNS reduced microglial activation, including Iba-1 and CD68, at 24 h in a manner similar to other VNS approaches [13, 37, 38]. These effects on glia activation may result from the systemic anti-inflammatory effects of VNS leading to a reduction in the overall neuroinflammatory burden, including Toll-like receptors signaling, rather than through a direct action as mediated through α7 nAChRs on microglia cells.…”

“…VNS commonly requires surgical implantation of electrodes around the cervical vagus and has been reported both to attenuate systemic inflammation after LPS treatment [12] and reduce neuroinflammation in rodent models [13]. Although this approach provides direct nerve stimulation, the procedure is invasive and not amenable to acute or ambulatory settings.…”

Baroreflex stimulation attenuates central but not peripheral inflammation in conscious endotoxemic rats

“…“Electroceuticals” have been considered a promising future for treating a number of diseases including central inflammatory and neurological disorders (Famm et al, 2013). Recent studies showed that electrical stimulation of peripheral nerves (including vagus) or direct brain stimulation, induces protective effects in ischemic stroke, traumatic brain injury, as well as in experimental cerebral ischemia and reperfusion (Jiang et al, 2014; Meneses et al, 2016; Notturno et al, 2014; Schweighöfer et al, 2016). …”

Sepsis: developing new alternatives to reduce neuroinflammation and attenuate brain injury

“…Additionally, TNF‐α inhibition has been found to protect the BBB, reducing inflammation and cerebral edema . Two novel strategies to control brain inflammation, described in detail below, have been recently studied in our research group …”

“…Considering the possible benefits of a tight control of NI, we propose two approaches for its modulation during septic processes, aiming to improve the disease outcome. One of them involves administering low doses of an anti‐inflammatory drug directly to the CNS by the intranasal route; the other one employs electrical stimulation of the vagus nerve …”