Vagus nerve stimulation in cerebral stroke:biological mechanisms,therapeutic modalities,clinical applications,and future directions

Stroke is a major disorder of the central nervous system that poses a serious threat to human life and quality of life.Many stro ke victims are left with long-term neurological dysfunction,which adversely affects the well-being of the individual and the broader socioeconomic impact.Currently,poststroke brain dysfunction is a major and difficult area of treatment.Vagus nerve stimulation is a Food and Drug Administration-approved exploratory treatment option for autis m,refractory depression,epilepsy,and Alzheimer’s disease.It is expected to be a novel therapeutic technique for the treatment of stroke owing to its association with multiple mechanisms such as alte ring neurotransmitters and the plasticity of central neuro ns.In animal models of acute ischemic stroke,vagus nerve stimulation has been shown to reduce infarct size,reduce post-stroke neurological damage,and improve learning and memory capacity in rats with stroke by reducing the inflammatory response,regulating bloodbrain barrier permeability,and promoting angiogenesis and neurogenesis.At present,vagus nerve stimulation includes both invasive and non-invasive vagus nerve stimulation.Clinical studies have found that invasive vagus nerve stimulation combined with rehabilitation therapy is effective in im proving upper limb motor and cognitive abilities in stroke patients.Further clinical studies have shown that non-invasive vagus nerve stimulation,including ear/ce rvical vagus nerve stimulation,can stimulate vagal projections to the central nervous system similarly to invasive vagus nerve stimulation and can have the same effect.In this paper,we first describe the multiple effects of vagus nerve stimulation in stroke,and then discuss in depth its neuroprotective mechanisms in ischemic stroke.We go on to outline the res ults of the current major clinical applications of invasive and non-invasive vagus nerve stimulation.Finally,we provide a more comprehensive evaluation of the advantages and disadvantages of different types of vagus nerve stimulation in the treatment of cerebral ischemia and provide an outlook on the developmental trends.We believe that vagus nerve stimulation,as an effective treatment for stroke,will be widely used in clinical practice to promote the recovery of stroke patients and reduce the incidence of disability.

Outcomes and efficacy of magnetic resonance imaging-compatible sacral nerve stimulator for management of fecal incontinence: A multi-institutional study

BACKGROUND Fecal incontinence(FI)is an involuntary passage of fecal matter which can have a significant impact on a patient’s quality of life.Many modalities of treatment exist for FI.Sacral nerve stimulation is a well-established treatment for FI.Given the increased need of magnetic resonance imaging(MRI)for diagnostics,the In-terStim which was previously used in sacral nerve stimulation was limited by MRI incompatibility.Medtronic MRI-compatible InterStim was approved by the United States Food and Drug Administration in August 2020 and has been widely used.AIM To evaluate the efficacy,outcomes and complications of the MRI-compatible InterStim.METHODS Data of patients who underwent MRI-compatible Medtronic InterStim placement at UPMC Williamsport,University of Minnesota,Advocate Lutheran General Hospital,and University of Wisconsin-Madison was pooled and analyzed.Patient demographics,clinical features,surgical techniques,complications,and outcomes were analyzed.Strengthening the Reporting of Observational studies in Epidemiology(STROBE)cross-sectional reporting guidelines were used.RESULTS Seventy-three patients had the InterStim implanted.The mean age was 63.29±12.2 years.Fifty-seven(78.1%)patients were females and forty-two(57.5%)patients had diabetes.In addition to incontinence,overlapping symptoms included diarrhea(23.3%),fecal urgency(58.9%),and urinary incontinence(28.8%).Fifteen(20.5%)patients underwent Peripheral Nerve Evaluation before proceeding to definite implant placement.Thirty-two(43.8%)patients underwent rechargeable InterStim placement.Three(4.1%)patients needed removal of the implant.Migration of the external lead connection was observed in 7(9.6%)patients after the stage I procedure.The explanation for one patient was due to infection.Seven(9.6%)patients had other complications like nerve pain,hematoma,infection,lead fracture,and bleeding.The mean follow-up was 6.62±3.5 mo.Sixty-eight(93.2%)patients reported significant improvement of symptoms on follow-up evaluation.CONCLUSION This study shows promising results with significant symptom improvement,good efficacy and good patient outcomes with low complication rates while using MRI compatible InterStim for FI.Further long-term follow-up and future studies with a larger patient population is recommended.

Millimetric devices for nerve stimulation:a promising path towards miniaturization

Nerve stimulation is a rapidly developing field,demonstrating positive outcomes across several conditions.Despite potential benefits,current nerve stimulation devices are large,complicated,and are powered via implanted pulse generators.These facto rs necessitate invasive surgical implantation and limit potential applications.Reducing nerve stimulation devices to millimetric sizes would make these interventions less invasive and facilitate broader therapeutic applications.However,device miniaturization presents a serious engineering challenge.This review presents significant advancements from several groups that have overcome this challenge and developed millimetricsized nerve stimulation devices.These are based on antennas,mini-coils,magneto-electric and optoelectronic materials,or receive ultrasound power.We highlight key design elements,findings from pilot studies,and present several considerations for future applications of these devices.

Evaluating the Impact of Transcutaneous Electrical Nerve Stimulation on Patients Undergoing Inguinal Hernia Surgery: A Meta- Analysis of Randomized Controlled Trials

Objective:A comprehensive meta-analysis based on the latest randomized controlled trials(RCTs)was conducted to investigate the effects of transcutaneous electrical nerve stimulation(TENS)on patients undergoing treatment after inguinal hernia surgery.Methods:A detailed search of Embase,PubMed,Web of Science,and the Cochrane Library was performed for RCTs investigating the use of TENS during inguinal hernia surgery up to September 28,2021.The Cochrane tool was applied to assess the risk of bias in the included studies.Results:Seven eligible RCTs with a total of 379 cases were included.The meta-analysis showed a mean difference(MD)in VAS of-1.61[95%CI:-2.20-1.02,P<0.00001]at 2 hours post-operation,VAS MD=-1.33 at 4 hours post-operation[95%CI:-2.84-0.18,P=0.09],VAS MD=-2.36 at 8 hours post-operation[95%CI:-4.04-0.69,P=0.006],and VAS MD=-1.75 at 24 hours post-operation[95%CI:-2.64-0.85,P=0.0001].The cortisol level MD at 24 hours post-operation was-52.56[95%CI:-168.8-63.76,P=0.38].Conclusion:TENS significantly reduces postoperative pain following inguinal hernia surgery and promotes patient recovery.TENS is recommended for patients undergoing inguinal hernia surgery.However,further high-quality studies are needed to confirm additional effects.

Inhibiting effect of vagal nerve stimulation to seizures in epileptic process of rats

Objective Our previous work suggested that sensitivity of hippocampal neurons is changed in process of epileptic activities,and closely parallel to the dynamic characteristic of epileptic activity of the neurons.This study investigated the sensitivity of epileptic brain to vagal nerve stimulation（VNS）in epileptic process.Methods Epileptic model was evoked by penicillin.Left vagal nerves were stimulated to inhibit the seizures induced by penicillin.The electrocorticography（ECoG）and electromyography（EMG）were recorded to analyze inhibiting effect of VNS in epileptic process.Results It was found that VNS could inhibit the seizures caused by penicillin,and the inhibiting effect of VNS to seizures increased as the vagal nerve stimulating time prolonged.It was also found that the inhibiting effect of VNS to seizures decreased in epileptic process.Conclusion The results suggested that the sensitivity of epileptic brain to VNS was different in epileptic process.The inhibiting effect of VNS to seizure decreased as the development of seizures.

Efficacy and safety of transcutaneous auricular vagus nerve stimulation combined with conventional rehabilitation training in acute stroke patients: a randomized controlled trial conducted for 1 year involving 60 patients

Transcutaneous auricular vagus nerve stimulation(ta-VNS)is a novel noninvasive treat-ment for stroke that directly stimulates the peripheral auricular branch of the vagus nerve.There have been recent reports that ta-VNS combined with conventional rehabilitation training promotes the recovery of neurological function of patients with acute stroke.However,these were small-sample-sized studies on the recovery of neurological function in patients after percutaneous vagus nerve stimulation in the subacute and chronic phases after stroke.This double-blinded randomized controlled trial involved 60 acute ischemic or hemorrhagic stroke patients aged 18-80 years who received treatment in the Second Affiliated Hospital of Chongqing Medical University.The subjects were randomly assigned to receive ta-VNS or sham ta-VNS combined with conventional rehabilitation training.The follow-up results over 1 year revealed that ta-VNS combined with conventional rehabilitation training greatly improved the recovery of motor and sensory functions and emotional responses compared with sham ta-VNS combined with conventional rehabilitation training.There were no obvious side effects.These findings suggest that ta-VNS combined with conventional rehabilitation training for the treatment of acute ischemic or hemorrhagic stroke patients is safe and effective.

Resuscitation therapy for traumatic brain injuryinduced coma in rats:mechanisms of median nerve electrical stimulation

In this study, rats were put into traumatic brain injury-induced coma and treated with median nerve electrical stimulation. We explored the wake-promoting effect, and possible mechanisms, of median nerve electrical stimulation. Electrical stimulation upregulated the expression levels of orexin-A and its receptor OX1R in the rat prefrontal cortex. Orexin-A expression gradually in-creased with increasing stimulation, while OX1R expression reached a peak at 12 hours and then decreased. In addition, after the OX1R antagonist, SB334867, was injected into the brain of rats after traumatic brain injury, fewer rats were restored to consciousness, and orexin-A and OXIR expression in the prefrontal cortex was downregulated. Our ifndings indicate that median nerve electrical stimulation induced an up-regulation of orexin-A and OX1R expression in the pre-frontal cortex of traumatic brain injury-induced coma rats, which may be a potential mechanism involved in the wake-promoting effects of median nerve electrical stimulation.

Wake-promoting effects of vagus nerve stimulation after traumatic brain injury: upregulation of orexin-A and orexin receptor type 1 expression in the prefrontal cortex

Orexins, produced in the lateral hypothalamus, are important neuropeptides that participate in the sleep/wake cycle, and their expres- sion coincides with the projection area of the vagus nerve in the brain. Vagus nerve stimulation has been shown to decrease the amounts of daytime sleep and rapid eye movement in epilepsy patients with traumatic brain injury. In the present study, we investigated whether vagus nerve stimulation promotes wakefulness and affects orexin expression. A rat model of traumatic brain injury was established using the free fall drop method. In the stimulated group, rats with traumatic brain injury received vagus nerve stimulation （frequency, 30 Hz, current, 1.0 mA; pulse width, 0.5 ms; total stimulation time, 15 minutes）. In the antagonist group, rats with traumatic brain injury were intracerebroventricularly injected with the orexin receptor type 1 （OXIR） antagonist SB334867 and received vagus nerve stimulation. Changes in consciousness were observed after stimulation in each group. Enzyme-linked immunosorbent assay, western blot assay and immunohistochemistry were used to assess the levels of orexin-A and OX1R expression in the prefrontal cortex. In the stimulated group, consciousness was substantially improved, orexin-A protein expression gradually increased within 24 hours after injury and OX1R expres- sion reached a peak at 12 hours, compared with rats subjected to traumatic brain injury only. In the antagonist group, the wake-promoting effect of vagus nerve stimulation was diminished, and orexin-A and OX1R expression were decreased, compared with that of the stim- ulated group. Taken together, our findings suggest that vagus nerve stimulation promotes the recovery of consciousness in comatose rats after traumatic brain injury. The upregulation of orexin-A and OXIR expression in the prefrontal cortex might be involved in the wake-promoting effects of vagus nerve stimulation.

Electrical stimulation of the vagus nerve protects against cerebral ischemic injury through an anti-inflammatory mechanism

Vagus nerve stimulation exerts protective effects against ischemic brain injury; however, the underlying mechanisms remain unclear. In this study, a rat model of focal cerebral ischemia was established using the occlusion method, and the right vagus nerve was given electrical stimula-tion （constant current of 0.5 mA; pulse width, 0.5 ms; frequency, 20 Hz; duration, 30 seconds; every 5 minutes for a total of 60 minutes） 30 minutes, 12 hours, and 1, 2, 3, 7 and 14 days after surgery. Electrical stimulation of the vagus nerve substantially reduced infarct volume, improved neurological function, and decreased the expression levels of tumor necrosis factor-α and in-terleukin-6 in rats with focal cerebral ischemia. The experimental findings indicate that the neuroprotective effect of vagus nerve stimulation following cerebral ischemia may be associated with the inhibition of tumor necrosis factor-α and interleukin-6 expression.

The mechanisms through which auricular vagus nerve stimulation protects against cerebral ischemia/reperfusion injury

Previous studies have shown that vagus nerve stimulation can improve patients' locomotor function.The stimulation of the auricular vagus nerve,which is the only superficial branch of the vagus nerve,may have similar effects to vagus nerve stimulation.However,the precise mechanisms remain poorly understood.In this study,rat models of cerebral ischemia/reperfusion injury were established by modified Longa ligation.Twenty-four hours later,7-day auricular vagus nerve stimulation was performed.The results showed that auricular vagus nerve stimulation promoted the secretion of acetylcholine,inhibited the secretion of interleukin-1β,interleukin-6,and tumor necrosis factor-α,and reduced connexin 43 phosphorylation in the ischemic penumbra and motor cortex,promoting locomotor function recovery in rats with cerebral ischemia/reperfusion injury.These findings suggested that auricular vagus nerve stimulation promotes the recovery of locomotor function in rats with cerebral ischemia/reperfusion injury by altering the secretion of acetylcholine and inflammatory factors and the phosphorylation of connexin 43.This study was approved by the Animal Use and Management Committee of Shanghai University of Traditional Chinese Medicine on November 8,2019(approval No.PZSHUTCM191108014).

Neuroprotective effects of vagus nerve stimulation on traumatic brain injury

Previous studies have shown that vagus nerve stimulation can improve the prognosis of trau- matic brain injury. The aim of this study was to elucidate the mechanism of the neuroprotective effects of vagus nerve stimulation in rabbits with brain explosive injury. Rabbits with brain ex- plosive injury received continuous stimulation （10 V, 5 Hz, 5 ms, 20 minutes） of the right cervical vagus nerve. Tumor necrosis factor-a, interleukin-l~ and interleukin-10 concentrations were detected in serum and brain tissues, and water content in brain tissues was measured. Results showed that vagus nerve stimulation could reduce the degree of brain edema, decrease tumor necrosis factor-a and interleukin-1β concentrations, and increase interleukin-10 concentration after brain explosive injury in rabbits. These data suggest that vagus nerve stimulation may exert neuroprotective effects against explosive injury via regulating the expression of tumor necrosis factor-a, interleukin-1 β and interleukin-10 in the serum and brain tissue.

An ultrasound-guided percutaneous electrical nerve stimulation regimen devised using finite element modeling promotes functional recovery after median nerve transection

Percutaneous electrical nerve stimulation of an injured nerve can promote and accelerate peripheral nerve regeneration and improve function.When performing acupuncture and moxibustion,locating the injured nerve using ultrasound before percutaneous nerve stimulation can help prevent further injury to an already injured nerve.However,stimulation parameters have not been standardized.In this study,we constructed a multi-layer human forearm model using finite element modeling.Taking current density and activated function as optimization indicators,the optimal percutaneous nerve stimulation parameters were established.The optimal parameters were parallel placement located 3 cm apart with the injury site at the midpoint between the needles.To validate the efficacy of this regimen,we performed a randomized controlled trial in 23 patients with median nerve transection who underwent neurorrhaphy.Patients who received conventional rehabilitation combined with percutaneous electrical nerve stimulation experienced greater improvement in sensory function,motor function,and grip strength than those who received conventional rehabilitation combined with transcutaneous electrical nerve stimulation.These findings suggest that the percutaneous electrical nerve stimulation regimen established in this study can improve global median nerve function in patients with median nerve transection.

Ultrasound Guidance and Nerve Stimulation Combined Versus Nerve Stimulation alone for Lumbar Plexus Block:A Randomized Controlled Trial

A nerve stimulation-guided lumbar plexus block is a well-established technique.It is not clear whether ultrasound guidance has additional value for this deep block technique.This study aimed to examine whether ultrasound guidance using a paramedian transverse scan through the intertransverse space(PMTS-ITS)approach in combination with nerve stimulation reduces the onset time of a complete sensory block.Forty-four patients who were scheduled to undergo arthroscopic knee surgery with an ultrasound visibility score(UVS)of≥10 for the lumbar plexus were enrolled and randomly allocated to the ultrasound guidance with nerve stimulation group(group U-N)or nerve stimulation group(group N)in this prospective,randomized,parallel-group,active-controlled study.The primary outcome was the onset time of a complete sensory block.The results showed that the onset time of a complete sensory block to pinprick and cold was 10(10–40)min and 10(10–40)min in group U-N,respectively,and 30(10–40)min and 20(10–40)min in group N(P=0.005,P=0.004),respectively.The performance time was 658±87 s in group U-N and 528±97 s in group N(P<0.001).There was no(0%)patient who required 5 or more needle passes in group U-N and 6(27.3%)in group N(P=0.028).The block failure rate was 9.1%in group U-N and 31.8%in group N(P>0.05).In conclusion,ultrasound guidance using the PMTS-ITS approach in combination with nerve stimulation led to a faster onset of a complete sensory block than nerve stimulation alone for a lumbar plexus block in patients with a UVS≥10.Ultrasound guidance with nerve stimulation significantly decreased the number of patients who required 5 or more needle passes.

A randomized trial comparing the Tennant Biomodulator to transcutaneous electrical nerve stimulation and traditional Chinese acupuncture for the treatment of chronic pain in military service members

Background:The present investigation tested the efficacy of the Tennant Biomodulator,a novel pain management intervention that uses biofeedback-modulated electrical stimulation,to reduce chronic pain and its psychosocial sequelae in a sample of current and former military service members.The Tennant Biomodulator used on its most basic setting was compared to two commonly used,non-pharmacological pain treatments—traditional Chinese acupuncture and transcutaneous electrical nerve stimulation(TENS)—in a comparative efficacy,randomized,open-label trial.Methods:Participants included 100 active duty and retired service men and women with chronic pain undergoing treatment at the Brooke Army Medical Center in Texas,USA,randomly assigned to receive six,weekly sessions of either Tennant Biomodulator treatment,traditional Chinese acupuncture,or TENS,in addition to usual care.Recruitment was conducted between May 2010 to September 2013.Outcome measures were collected at intake,before and after each treatment session,and at a 1-month follow-up.Intent-to-treat analyses were used throughout,with mixed models used to investigate main effects of group,time,and group×time interactions with consideration given to quadratic effects.Outcomes measured included ratings of chronic pain,pain-related functional disability,and symptoms of post-traumatic stress disorder(PTSD)and depression.Results:On average,regardless of their treatment group,participants exhibited a 16%reduction in pain measured by the Brooke Army Medical Center’s Clinic Pain Log[F(1,335)=55.7,P<0.0001]and an 11%reduction in pain-related disability measured by the Million Visual Analog Scale[MVAS:F(1,84)=28.3,P<0.0001]from baseline to the end of treatment,but no one treatment performed better than the other,and the reductions in pain and pain-related disability were largely lost by 1-month follow-up.Symptoms of PTSD and depression did not change significantly as a function of time or group.Conclusions:Findings build on previous work suggesting that traditional Chinese acupuncture and TENS can reduce pain and its functional sequelae without risks associated with pharmacological pain management.The Tennant Biomodulator used on its most basic setting performs as well as these other interventions.Based on the present findings,large,randomized controlled trials on the Tennant Biomodulator are indicated.Future work should test this device using its full range of settings for pain-related psychological health.Trial registration:Clincialtrials.gov(NCT01752010);registered December 14,2012.

Vagus nerve stimulation is a potential treatment for ischemic stroke

Microglia are the brain’s primary innate immune cells,and they are activated and affect pro-inflammatory phenotype or regulatory phenotype after ischemic stroke.Vagus nerve stimulation was shown to activate microglial phenotypic changes and exhibit neuroprotective effects in ischemia/reperfusion injury.In this study,we established rat models of ischemic stroke by occlusion of the middle cerebral artery and performed vagus nerve stimulation 30 minutes after modeling.We found that vagus nerve stimulation caused a shift from a pro-inflammatory phenotype to a regulatory phenotype in microglia in the ischemic penumbra.Vagus nerve stimulation decreased the levels of pro-inflammatory phenotype markers inducible nitric oxide synthase and tumor necrosis factorαand increased the expression of regulatory phenotype markers arginase 1 and transforming growth factorβthrough activatingα7 nicotinic acetylcholine receptor expression.Additionally,α7 nicotinic acetylcholine receptor blockade reduced the inhibition of Toll-like receptor 4/nuclear factor kappa-B pathwayassociated proteins,including Toll-like receptor 4,myeloid differentiation factor 88,I kappa B alpha,and phosphorylated-I kappa B alpha,and also weakened the neuroprotective effects of vagus nerve stimulation in ischemic stroke.Vagus nerve stimulation inhibited Toll-like receptor 4/nuclear factor kappa-B expression through activatingα7 nicotinic acetylcholine receptor and regulated microglial polarization after ischemic stroke,thereby playing a role in the treatment of ischemic stroke.Findings from this study confirm the mechanism underlying vagus nerve stimulation against ischemic stroke.

Left-sided vagus nerve stimulation improves cardiopulmonary resuscitation outcomes in rats as effectively as right-sided vagus nerve stimulation

BACKGROUND: Our group previously reported that right-sided vagus nerve stimulation(RVNS) significantly improved outcomes after cardiopulmonary resuscitation(CPR) in a rat model of cardiac arrest(CA). However, whether left-sided vagus nerve stimulation(LVNS) could achieve the same effect as RVNS in CPR outcomes remains unknown.METHODS: A rat model of CA was established using modified percutaneous epicardial electrical stimulation to induce ventricular fibrillation(VF). Rats were treated with LVNS or RVNS for 30 minutes before the induction of VF. All animals were observed closely within 72 hours after return of spontaneous circulation(ROSC), and their health and behavior were evaluated every 24 hours.RESULTS: Compared with those in the RVNS group, the hemodynamic measurements in the LVNS group decreased more notably. Vagus nerve stimulation(VNS) decreased the serum levels of tumor necrosis factor-alpha(TNF-α) and the arrhythmia score, and attenuated inflammatory infiltration in myocardial tissue after ROSC, regardless of the side of stimulation, compared with findings in the CPR group. Both LVNS and RVNS ameliorated myocardial function and increased the expression of α-7 nicotinic acetylcholine receptor in the myocardium after ROSC. Moreover, a clear improvement in 72-hour survival was shown with VNS pre-treatment, with no significant difference in efficacy when comparing the laterality of stimulation. CONCLUSIONS: LVNS may have similar effects as RVNS on improving outcomes after CPR.

Sphincteroplasty for fecal incontinence in the era of sacral nerve modulation

The role of sphincteroplasty in the treatment of patients with fecal incontinence due to anal sphincter defects has been questioned because the success rate declines in the long-term.A new emerging treatment for fecal incontinence,sacral nerve stimulation,has been shown to be effective in these patients.However,the success rate of sphincteroplasty may depend of several patient-related and surgical-related factors and the outcome from sphincteroplasty has been evaluated differently(with qualitative data) from that after sacral nerve stimulation(quantitative data using scoring systems and quality of life).Furthermore,the data available so far on the longterm success rate after sacral nerve modulation do not differ substantially from those after sphincteroplasty.The actual data do not support the replacement of sphincteroplasty with sacral nerve stimulation in patients with fecal incontinence secondary to sphincter defects.

Ultra-early amplitude decrement after repetitive nerve stimulation supports early neuromuscular junction injury in amyotrophic lateral sclerosis:a prospective cross-sectional study

The dying-back hypothesis holds that the damage to neuromuscular junctions and distal axons in amyotrophic lateral sclerosis occurs at the earliest stage of the disease.Previous basic studies have confirmed early damage to neuromuscular junctions,but it is difficult to obtain such evidence directly in clinical practice.In this prospective cross-sectional study,we recruited 22 patients with early amyotrophic lateral sclerosis with disease duration < 12 months and with clinical symptoms limited to the upper limbs.We also recruited 32 healthy controls.Repetitive nerve stimulation was performed,and patients were followed for 12 months.We found a significant change in the response to repetitive nerve stimulation in amyotrophic lateral sclerosis patients without spontaneous electromyographic activity.Patients that were prone to denervation had an increased decrement response of target muscles after repetitive nerve stimulation.These results suggest that changes in response to repetitive nerve stimulation may occur before denervation in amyotrophic lateral sclerosis patients.The damage to lower motor neurons is more obvious in patients with a higher percentage of repetitive never stimulation-related amplitude decrements.This study was approved by the Institutional Ethics Committee of Peking University Third Hospital(approval No.M2017198) on August 24,2017.

Vagus nerve stimulation protects against cerebral injury after cardiopulmonary resuscitation by inhibiting inflammation through the TLR4/NF-κB and α7nAChR/JAK2 signaling pathways

BACKGROUND: Our previous research proved that vagus nerve stimulation(VNS) improved the neurological outcome after cardiopulmonary resuscitation(CPR) by activating α7 nicotinic acetylcholine receptor(α7nAChR) in a rat model, but the underlying mechanism of VNS in neuroprotection after CPR remains unclear.METHODS: In vivo, we established a mouse model of cardiac arrest(CA)/CPR to observe the survival rate, and the changes in inflammatory factors and brain tissue after VNS treatment. In vitro, we examined the effects of α7nAChR agonist on ischemia/reperfusion(I/R)-induced inflammation in BV2 cells under oxygen-glucose deprivation/reoxygenation(OGD/R) conditions. We observed the changes in cell survival rate, the levels of inflammatory factors, and the expressions of α7nAChR/Janus kinase 2(JAK2) and toll-like receptor 4(TLR4)/nuclear factor-κB(NF-κB).RESULTS: In vivo, VNS preconditioning enhanced functional recovery, improved the survival rate, and reduced hippocampal CA1 cell damage, and the levels of inflammatory mediators after CA/CPR. The application of α7nAChR agonists provided similar effects against cerebral injury after the return of spontaneous circulation(ROSC), while α7nAChR antagonists reversed these neuroprotective impacts. The in vitro results mostly matched the findings in vivo. OGD/R increased the expression of tumor necrosis factor-alpha(TNF-α), TLR4 and NF-κB p65. When nicotine was added to the OGD/R model, the expression of TLR4, NF-κB p65, and TNF-α decreased, while the phosphorylation of JAK2 increased, which was prevented by preconditioning with α7nAChR or JAK2 antagonists.CONCLUSION: The neuroprotective effect of VNS correlated with the activation of α7nAChR. VNS may alleviate cerebral IR injury by inhibiting TLR4/NF-κB and activating the α7nAChR/JAK2 signaling pathway.

Delayed peripheral nerve repair: methods, including surgical ‘cross-bridging' to promote nerve regeneration

Despite the capacity of Schwann cells to support peripheral nerve regeneration, functional recovery after nerve injuries is frequently poor, especially for proximal injuries that require regenerating axons to grow over long distances to reinnervate distal targets. Nerve transfers, where small fascicles from an adjacent intact nerve are coapted to the nerve stump of a nearby denervated muscle, allow for functional return but at the expense of reduced numbers of innervating nerves. A 1-hour period of 20 Hz electrical nerve stimulation via electrodes proximal to an injury site accelerates axon outgrowth to hasten target reinnervation in rats and humans, even after delayed surgery. A novel strategy of enticing donor axons from an otherwise intact nerve to grow through small nerve grafts（cross-bridges） into a denervated nerve stump, promotes improved axon regeneration after delayed nerve repair. The efficacy of this technique has been demonstrated in a rat model and is now in clinical use in patients undergoing cross-face nerve grafting for facial paralysis. In conclusion, brief electrical stimulation, combined with the surgical technique of promoting the regeneration of some donor axons to ‘protect＇ chronically denervated Schwa nn cells, improves nerve regeneration and, in turn, functional outcomes in the management of peripheral nerve injuries.