Valproic acid protects neurons and promotes neuronal regeneration after brachial plexus avulsion

Valproic acid has been shown to exert neuroprotective effects and promote neurite outgrowth in several peripheral nerve injury models. However, whether valproic acid can exert its beneficial effect on neurons after brachial plexus avulsion injury is currently unknown. In this study, brachial plexus root avulsion models, established in Wistar rats, were administered daily with valproic acid dis-solved in drinking water （300 mg/kg） or normal water. On days 1, 2, 3, 7, 14 and 28 after avulsion injury, tissues of the C 5-T 1 spinal cord segments of the avulsion injured side were harvested to in-vestigate the expression of Bcl-2, c-Jun and growth associated protein 43 by real-time PCR and western blot assay. Results showed that valproic acid significantly increased the expression of Bcl-2 and growth associated protein 43, and reduced the c-Jun expression after brachial plexus avulsion. Our findings indicate that valproic acid can protect neurons in the spinal cord and enhance neuronal regeneration fol owing brachial plexus root avulsion.

Peripheral BDNF Regulates Somatosensory–Sympathetic Coupling in Brachial Plexus Avulsion-Induced Neuropathic Pain

Brachial plexus avulsion(BPA)is a combined injury involving the central and peripheral nervous systems.Patients with BPA often experience severe neuropathic pain(NP)in the affected limb.NP is insensitive to the existing treatments,which makes it a challenge to researchers and clinicians.Accumulated evidence shows that a BPA-induced pain state is often accompanied by sympathetic nervous dysfunction,which suggests that the excitation state of the sympathetic nervous system is correlated with the existence of NP.However,the mechanism of how somatosensory neural crosstalk with the sympathetic nerve at the peripheral level remains unclear.In this study,through using a novel BPA C7 root avulsion mouse model,we found that the expression of BDNF and its receptor TrκB in the DRGs of the BPA mice increased,and the markers of sympathetic nervous system activity includingα1 andα2 adrenergic receptors(α1-AR andα2-AR)also increased after BPA.The phenomenon of superexcitation of the sympathetic nervous system,including hypothermia and edema of the affected extremity,was also observed in BPA mice by using CatWalk gait analysis,an infrared thermometer,and an edema evaluation.Genetic knockdown of BDNF in DRGs not only reversed the mechanical allodynia but also alleviated the hypothermia and edema of the affected extremity in BPA mice.Further,intraperitoneal injection of adrenergic receptor inhibitors decreased neuronal excitability in patch clamp recording and reversed the mechanical allodynia of BPA mice.In another branch experiment,we also found the elevated expression of BDNF,TrκB,TH,α1-AR,andα2-AR in DRG tissues from BPA patients compared with normal human DRGs through western blot and immunohistochemistry.Our results revealed that peripheral BDNF is a key molecule in the regulation of somatosensory-sympathetic coupling in BPA-induced NP.This study also opens a novel analgesic target(BDNF)in the treatment of this pain with fewer complications,which has great potential for clinical transformation.

Increased EZH2 Levels in Anterior Cingulate Cortex Microglia Aggravate Neuropathic Pain by Inhibiting Autophagy Following Brachial Plexus Avulsion in Rats

After brachial plexus avulsion(BPA),microglia induce inflammation,initiating and maintaining neuropathic pain.EZH2(enhancer of zeste homolog 2) has been implicated in inflammation and neuropathic pain,but the mechanisms by which it regulates neuropathic pain remain unclear.Here,we found that EZH2 levels were markedly upregulated during BPA-induced neuropathic pain in vivo and in vitro,stimulating pro-inflammatory cytokines(IL-1β,TNF-α,and IL-6) secretion in vivo.In rats with BPAinduced neuropathic pain,mechanical and cold hypersensitivities were induced by EZH2 upregulation and inhibited by EZH2 downregulation in the anterior cingulate cortex.Microglial autophagy was also significantly inhibited,with EZH2 inhibition activating autophagy and reducing neuroinflammation in vivo.However,this effect was impaired by inhibiting autophagy with 3-methyladenine,suggesting that the MTOR signaling pathway is a functional target of EZH2.These data suggest that EZH2 regulates neuroinflammation and neuropathic pain via a novel MTOR-mediated autophagy signaling pathway,providing a promising approach for managing neuropathic pain.

Brain glucose metabolic changes associated with chronic spontaneous pain due to brachial plexus avulsion： a preliminary positron emission tomography study

Background Previous brain imaging studies suggested that the brain activity underlying the perception of chronic pain may differ from that underlying acute pain. To investigate the brain regions involved in chronic spontaneous pain due to brachial plexus avulsion （BPA）, fluorine-18^fluorodeoxyglucose （18^F-FDG） positron emission tomography （PET） scanning was applied to determine the glucose metabolic changes in patients with pain due to BPA.Methods Six right-handed patients with chronic spontaneous pain due to left-BPA and twelve right-handed age- and sex-matched healthy control subjects participated in the 18^F-FDG PET study. The patients were rated by visual analog scale （VAS） during scanning and Hamilton depression scale and Hamilton anxiety scale after scanning. Statistical parametric mapping 2 （SPM2） was applied for data analysis. Results Compared with healthy subjects, the patients had significant glucose metabolism decreases in the right thalamus and SI （P 〈0.001, uncorrected）, and significant glucose metabolism increases in the right orbitofrontal cortex （OFC） （BAll）, left rostral insula cortex and left dorsolateral prefrontal cortex （DLPFC） （BA10/46） （P 〈0.001, uncorrected）. Conclusion These findings suggest that the brain areas involved in emotion, attention and internal modulation of pain may be related to the chronic spontaneous pain due to BPA.

Penile erectile dysfunction after brachial plexus root avulsion injury in rats

Our previous studies have demonstrated that some male patients suffering from brachial plexus injury, particularly brachial plexus root avulsion, show erectile dysfunction to varying degrees. However, the underlying mechanism remains poorly understood. In this study, we evaluated the erectile function after establishing brachial plexus root avulsion models with or without spinal cord injury in rats. After these models were established, we administered apomorphine （via a sub- cutaneous injection in the neck） to observe changes in erectile function. Rats subjected to simple brachial plexus root avulsion or those subjected to brachial plexus root avulsion combined with spinal cord injury had significantly fewer erections than those subjected to the sham operation. Expression of neuronal nitric oxide synthase did not change in brachial plexus root avulsion rats. However, neuronal nitric oxide synthase expression was significantly decreased in brachial plexus root avulsion ＋ spinal cord injury rats. These findings suggest that a decrease in neuronal nitric oxide synthase expression in the penis may play a role in erectile dysfunction caused by the combi- nation of brachial plexus root avulsion and spinal cord injury.

Functional reconstruction following brachial plexus root avulsion

OBJECTIVE： To sum up the treatment of brachial plexus root avulsion and the progress in functional reconstruction and rehabilitation following brachial plexus root avulsion. DATA SOURCES： A search of Medline was performed to select functional reconstruction and rehabilitation following brachial plexus injury-related English articles published between January 1990 and July 2006, with key words of ＂brachial plexus injury, reconstruction and rehabilitation＂. Meanwhile, a computer-based search of CBM was carried out to select the similar Chinese articles published between January 1998 and July 2006, with key words of ＂brachial plexus injury, reconstruction and rehabilitation＂. STUDY SELECTION： The materials were checked primarily, and the literatures of functional reconstruction and rehabilitation of brachial plexus injury were selected and the full texts were retrieved. Inclusive criteria： ①Functional reconstruction following brachial plexus injury. ②Rehabilitation method of brachial plexus injury. Exclusive criteria： Reviews, repetitive study, and Meta analytical papers. DATA EXTRACTION： Forty-six literatures about functional reconstruction following brachial plexus injury were collected, and 36 of them met the inclusive criteria. DATA SYNTHESIS： Brachial plexus injury causes the complete or incomplete palsy of muscle of upper extremity. The treatment of brachial plexus is to displace not very important nerves to the distal end of very important nerve, called nerve transfer, which is an important method to treat brachial plexus injury. Postoperative rehabilitations consist of sensory training and motor functional training. It is very important to keep the initiativeness of exercise. Besides recovering peripheral nerve continuity by operation, combined treatment and accelerating neural regeneration, active motors of cerebral cortex is also the important factor to reconstruct peripheral nerve function. CONCLUSION： Consciously and actively strengthening functional exercise after operation is helpful to form cerebral plasticity and produce voluntary movements, can re-educate re-dominated muscle, obviously improves postoperative therapeutic effect and promote functional reconstruction.

Electroacupuncture attenuates neuropathic pain after brachial plexus injury

Electroacupuncture has traditionally been used to treat pain, but its effect on pain following brachial plexus injury is still unknown. In this study, rat models of an avulsion injury to the left brachial plexus root （associated with upper-limb chronic neuropathic pain） were given electroacupuncture stimulation at bilateral Quchi （LIll）, Hegu （LI04）, Zusanli （ST36） and Yanglingquan （GB34）. After electroacupuncture therapy, chronic neuropathic pain in the rats＇ upper limbs was significantly attenuated. Immunofluorescence staining showed that the expression of β-endorphins in the arcuate nucleus was significantly increased after therapy. Thus, experimental findings indi- cate that electroacupuncture can attenuate neuropathic pain after brachial plexus injury through upregulating β-endorphin expression.