Early Intervention of Cold-Water Swimming on Functional Recovery and Spinal Pain Modulation Following Brachial Plexus Avulsion in Rats.

Brachial plexus avulsion (BPA) causes peripheral nerve injury complications with motor and sensory dysfunction of the upper limb. Growing evidence has shown an active role played by cold-water swimming (CWS) in alleviating peripheral neuropathic pain and functional recovery. This study examined whether CWS could promote functional recovery and pain modulation through the reduction of neuroinflammation and microglial overactivation in dorsal horn neurons at the early-stage of BPA. After BPA surgery was performed on rats, they were assigned to CWS or sham training for 5 min twice a day for two weeks. Functional behavioral responses were tested before and after BPA surgery, and each week during training. Results after the two-week training program showed significant improvements in BPA-induced motor and sensory loss (p < 0.05), lower inflammatory cell infiltration, and vacuole formation in injured nerves among the BPA-CWS group. Moreover, BPA significantly increased the expression of SP and IBA1 in dorsal horn neurons (p < 0.05), whereas CWS prevented their overexpression in the BPA-CWS group. The present findings evidenced beneficial rehabilitative effects of CWS on functional recovery and pain modulation at early-stage BPA. The beneficial effects are partially related to inflammatory suppression and spinal modulation. The synergistic role of CWS combined with other management approaches merits further investigation.

Ultra-Low Frequency Transcutaneous Electrical Nerve Stimulation on Pain Modulation in a Rat Model with Myogenous Temporomandibular Dysfunction.

Masticatory myofascial pain (MMP) is one of the most common causes of chronic orofacial pain in patients with temporomandibular disorders. To explore the antinociceptive effects of ultra-low frequency transcutaneous electrical nerve stimulation (ULF-TENS) on alterations of pain-related biochemicals, electrophysiology and jaw-opening movement in an animal model with MMP, a total of 40 rats were randomly and equally assigned to four groups; i.e., animals with MMP receiving either ULF-TENS or sham treatment, as well as those with sham-MMP receiving either ULF-TENS or sham treatment. MMP was induced by electrically stimulated repetitive tetanic contraction of masticatory muscle for 14 days. ULF-TENS was then performed at myofascial trigger points of masticatory muscles for seven days. Measurable outcomes included maximum jaw-opening distance, prevalence of endplate noise (EPN), and immunohistochemistry for substance P (SP) and µ-opiate receptors (MOR) in parabrachial nucleus and c-Fos in rostral ventromedial medulla. There were significant improvements in maximum jaw-opening distance and EPN prevalence after ULF-TENS in animals with MMP. ULF-TENS also significantly reduced SP overexpression, increased MOR expression in parabrachial nucleus, and increased c-Fos expression in rostral ventromedial medulla. ULF-TENS may represent a novel and applicable therapeutic approach for improvement of orofacial pain induced by MMP.

Ultrasound Acupuncture for Oxaliplatin-induced Peripheral Neuropathy in Patients With Colorectal Cancer: A Pilot Study.

BACKGROUND: Oxaliplatin is frequently used in the treatment of metastatic colorectal cancer. However, peripheral neuropathy is a severe adverse effect of oxaliplatin that may persist and impact quality of life. OBJECTIVE: To assess the potential effects of ultrasound acupuncture for the alleviation of symptoms related to oxaliplatin-induced peripheral neuropathy (OIPN) among patients with metastatic colorectal cancer. DESIGN: Prospective cohort pilot study. SETTING: Education and research hospital. PARTICIPANTS: Patients with a diagnosis of stage II-IV colorectal cancer undergoing oxaliplatin-based treatment regimens who experienced OIPN symptoms (n = 17). INTERVENTIONS: Pulsed therapeutic ultrasound (1 MHz) at bilateral acupuncture points of PC6, PC7, BL60, and KI1 was administered for 5 minutes per point daily for 12 days. MAIN OUTCOME MEASUREMENTS: Pain Quality Assessment Scale (PQAS), Chemotherapy-induced Neurotoxicity Questionnaire (CINQ), quantitative touch-detection threshold, cold-trigger pain withdrawal latency, and quality of life (EORTC QLQ-C30) were measured at baseline (day 0), pre-intervention (day 12, post wash-out period), post-intervention (day 24), and final follow-up (day 54). A P value of less than .05 was considered statistically significant. RESULTS: Scores of PQAS and CINQ significantly improved after ultrasound acupuncture at post-intervention and follow-up compared to both baseline and pre-intervention. Similar trends were also observed for the quantitative sensory testing, where touch-detection threshold significantly decreased and cold-trigger pain withdrawal latency significantly increased after ultrasound acupuncture. Patients also showed an improvement on quality of life outcomes as measured by QLQ-C30 post-intervention and at follow-up. CONCLUSIONS: Ultrasound acupuncture could be an effective intervention for OIPN symptoms for patients with colorectal cancer. However, larger and randomized clinical trials with placebo controls are needed to confirm such effects.

Early intervention of swimming exercises attenuate articular cartilage destruction in a rat model of anterior cruciate ligament and meniscus knee injuries.

AIM: The anterior cruciate ligament (ACL) and meniscus injuries often cause post-traumatic knee osteoarthritis (PTOA), which can place great limitations on patients. But to date there is no effective therapy to delay the progression of cartilage destruction in PTOA. This study aimed to compare the effects of early versus delayed swimming exercise on the chondroprotective effects in a rat PTOA model with ACL and meniscus injuries. MAIN METHODS: Thirty-two adult male Sprague-Dawley rats received unilateral ACL transection and medial meniscectomy (ACLMT). These were randomly allocated to four groups: early swimming (eSW), delayed swimming (dSW), sham-operated early swimming (sham-eSW) and sham-operated delayed swimming (sham-dSW). Swimming (30 min per session) continuing for 28 days was started three days and three months after ACLMT surgery as a protocol for eSW and dSW intervention. Cartilage quality was assessed by Mankin HHGS examination (H&E, Safranin-O stain) and collagen type II (CoII) and matrix metalloproteases-13 (MMP13) immunohistochemistry. KEY FINDINGS: ACLMT induced the PTOA histopathological changes, inhibited CoII and enhanced MMP13 expressions in cartilage for both sham-eSW and sham-dSW groups. eSW intervention significantly enhanced CoII expression and suppressed MMP13 overexpression in superficial and transitional zones of cartilage, as well as better Mankin scores, corresponding to sham-swimming controls (P < 0.05). dSW intervention provided less enhancement of CoII expression and improvement of histopathological scoring, but significantly reduced MMP13 overexpression compared to animals in eSW (P < 0.05). SIGNIFICANCE: Early intervention by swimming at very early stages of cartilage damage provides greater benefits than delayed intervention when PTOA has already developed.

Early Intervention with Therapeutic Low-Intensity Pulsed Ultrasound in Halting the Progression of Post-traumatic Osteoarthritis in a Rat Model.

Anterior cruciate ligament (ACL) and meniscus injuries are highly correlated with post-traumatic knee osteoarthritis (PTOA). The aim of this study was to examine whether early intervention with low-intensity pulsed ultrasound (LIPUS) at an intensity of 0.1 W/cm2 helps delay PTOA progression. A PTOA model was established by ACL transection and meniscectomy in male Sprague-Dawley rats. LIPUS intervention (1.0 MHz, 0.1 W/cm2) started on the third day after surgery and continued for 4 consecutive wk. Histopathological analyses and immunoassays of collagen type II and matrix metallopeptidase 13 in joints were conducted. Results indicated that compared with the sham treatment, LIPUS significantly reduced Mankin scores, inflammatory cells and matrix metallopeptidase 13 expression and increased collagen type II expression in rats with PTOA (p < 0.05). Early intervention with LIPUS has beneficial effects on delaying cartilage degradation by reducing synovial inflammation and matrix metallopeptidase 13 expression, as well as enhancing collagen type II expression in cartilage.

Laser acupuncture attenuates oxaliplatin-induced peripheral neuropathy in patients with gastrointestinal cancer: a pilot prospective cohort study.

BACKGROUND: Oxaliplatin is a platinum compound that is widely used in the treatment of some solid tumours. Oxaliplatin-induced peripheral neuropathy (OIPN) in the upper and lower extremities is the major adverse side effect and represents the main dose-limiting factor of this drug. The aim of this single-arm study was to evaluate the feasibility and effects of laser acupuncture (LA) in the treatment of OIPN in patients with advanced gastrointestinal cancers. METHODS: 17 gastrointestinal cancer survivors (14 colorectal and 3 gastric cancers), who had been treated with oxaliplatin-based chemotherapies, were recruited. Low-level laser stimulation (50 mW) bilaterally at PC6, PC7, PC8, P9, LU11, SP6, KI3, BL60, KI1, and KI2 was administered for 20 min/point for 12 sessions over 4 weeks. The pain quality assessment scale (PQAS), chemotherapy-induced neurotoxicity questionnaire (CINQ), oxaliplatin-specific neurotoxicity scale (OSNS), quantitative touch-detection threshold (using von Frey filaments), and cold-triggered pain withdrawal latency (using the cold-water immersion test) were measured before and after completion of the 12 treatment sessions. RESULTS: PQAS, CINQ, and OSNS scores, as well as touch-detection threshold and cold-trigger pain withdrawal latency all improved significantly after LA in the cancer patients with OIPN (p<0.05). LA significantly relieved both oxaliplatin-induced cold and mechanical allodynia and also decreased the incidence and severity of neurotoxicity symptoms in the patients' upper and lower extremities and impact on their daily activities (all p<0.05). CONCLUSIONS: Following treatment with LA, neurotoxicity symptoms were significantly improved in cancer patients with OIPN. Further randomised controlled trials are needed to evaluate the role of LA as a therapeutic option in the management of OIPN.

Synergistic effects of low-level laser and mesenchymal stem cells on functional recovery in rats with crushed sciatic nerves.

Transplantation of mesenchymal stem cells (MSCs) has been proposed to exert beneficial effects on peripheral nerve regeneration after a peripheral nerve injury, but the functional recovery in the denervated limb is still limited. In this study, we used low-level laser therapy (LLLT) as an adjunct therapy for MSC transplantation on the functional recovery of crushed sciatic nerve in rats. Peripheral nerve injury was induced in 48 Sprague-Dawley rats by crushing the unilateral sciatic nerve, using a vessel clamp. The animals with crushed injury were randomly divided into four groups: control group, with no treatment; MSC group, treated with MSC alone; LLLT group, treated with LLLT alone; and MSCLLLT group, treated with a combination of MSC and LLLT. The sciatic function index (SFI), vertical activity of locomotion (VA) and ankle angle (AA) of rats were examined for functional assessments after treatment. Electrophysiological, morphological and S100 immunohistochemical studies were also conducted. The MSCLLLT group showed a greater recovery in SFI, VA and AA, with significant difference from MSC, LLLT and control groups (p < 0.05). Moreover, markedly enhanced electrophysiological function and expression of S100 immunoreactivity, as well as fewer inflammatory cells and less vacuole formation were also demonstrated after nerve crush injury in the MSCLLLT group when compared with the groups receiving a single treatment (p < 0.05). MSC transplantation combined with LLLT could achieve better results in functional recovery than a conventional treatment of MSC or LLLT alone. LLLT has a synergistic effect in providing greater functional recovery with MSC transplantation after nerve crush injury.

Enhanced functional recovery from sciatic nerve crush injury through a combined treatment of cold-water swimming and mesenchymal stem cell transplantation.

OBJECTIVE: Although regimens of stem cell implantation can elicit functional recovery following peripheral nerve injury, the degree of outcome is still limited. This study evaluated the synergistic effects of cold-water swimming (CWS) and mesenchymal stem cell (MSC) transplantation on functional recovery of crushed sciatic nerve in rats. METHOD: Forty Sprague-Dawley rats that had their sciatic nerve crushed during surgery were randomly divided into four groups: MSCCWS group, treated with combination of MSC and CWS; MSC group, treated with MSC alone; CWS group, treated with CWS alone; and non-treated group, without any treatments. The sciatic function index (SFI), vertical activity (VA), ankle activity (AA) and electrophysiological study were examined before, immediately after surgery, after the treatment and after 4  weeks from treatment. Morphological and S100 immunohistochemical studies were also performed. RESULTS: The MSCCWS group showed a greater improvement in SFI, VA, AA, peak amplitudes and onset latencies of compound muscle action potential (CMAP) in sciatic nerve and infiltration of immune cells with significant difference from the MSC, CWS and non-treated groups (P < 0.05). CONCLUSIONS: MSC transplantation combined with CWS could achieve better results in functional recovery than a single treatment of MSC alone or CWS alone in nerve crush injury.

Sitagliptin attenuates sympathetic innervation via modulating reactive oxygen species and interstitial adenosine in infarcted rat hearts.

We investigated whether sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, attenuates arrhythmias through inhibiting nerve growth factor (NGF) expression in post-infarcted normoglycemic rats, focusing on adenosine and reactive oxygen species production. DPP-4 bound adenosine deaminase has been shown to catalyse extracellular adenosine to inosine. DPP-4 inhibitors increased adenosine levels by inhibiting the complex formation. Normoglycemic male Wistar rats were subjected to coronary ligation and then randomized to either saline or sitagliptin in in vivo and ex vivo studies. Post-infarction was associated with increased oxidative stress, as measured by myocardial superoxide, nitrotyrosine and dihydroethidium fluorescent staining. Measurement of myocardial norepinephrine levels revealed a significant elevation in vehicle-treated infarcted rats compared with sham. Compared with vehicle, infarcted rats treated with sitagliptin significantly increased interstitial adenosine levels and attenuated oxidative stress. Sympathetic hyperinnervation was blunted after administering sitagliptin, as assessed by immunofluorescent analysis and western blotting and real-time quantitative RT-PCR of NGF. Arrhythmic scores in the sitagliptin-treated infarcted rats were significantly lower than those in vehicle. Ex vivo studies showed a similar effect of erythro-9-(2-hydroxy-3-nonyl) adenine (an adenosine deaminase inhibitor) to sitagliptin on attenuated levels of superoxide and NGF. Furthermore, the beneficial effects of sitagliptin on superoxide anion production and NGF levels can be reversed by 8-cyclopentyl-1,3-dipropulxanthine (adenosine A1 receptor antagonist) and exogenous hypoxanthine. Sitagliptin protects ventricular arrhythmias by attenuating sympathetic innervation via adenosine A1 receptor and xanthine oxidase-dependent pathways, which converge through the attenuated formation of superoxide in the non-diabetic infarcted rats.

Fluence-dependent effects of low-level laser therapy in myofascial trigger spots on modulation of biochemicals associated with pain in a rabbit model.

Evidence strongly supports that low-level laser therapy (LLLT) is an effective physical modality for the treatment of pain associated with myofascial trigger points (MTrP). However, the effect of laser fluence (energy intensity in J/cm(2)) on biochemical regulation related to pain is unclear. To better understand the biochemical mechanisms modulated by high- and low-fluence LLLT at myofascial trigger spots (MTrSs; similar to human MTrPs) in skeletal muscles of rabbits, the levels of ß-endorphin (ß-ep), substance P (SP), tumor necrosis factor-α (TNF-α), and cyclooxygenase-2 (COX-2) were investigated in this study. New Zealand rabbits (2.5-3.0 kg in weight) were used in this study. High-fluence LLLT (27 J/cm(2)), low-fluence LLLT (4.5 J/cm(2)), or sham operations were applied on MTrSs of biceps femoris of rabbits for five sessions (one session per day). Effects of LLLT at two different fluences on biceps femoris, dorsal root ganglion (DRG), and serum were determined by ß-ep, SP, TNF-α, and COX-2 immunoassays. LLLT irradiation with fluences of 4.5 and 27 J/cm(2) at MTrSs can significantly reduce SP level in DRG. LLLT with lower fluence of 4.5 J/cm(2) exerted lower levels of TNF-α and COX-2 expression in laser-treated muscle, but LLLT with higher fluence of 27 J/cm(2) elevated the levels of ß-ep in serum, DRG, and muscle. This study demonstrated fluence-dependent biochemical effects of LLLT in an animal model on management of myofascial pain. The findings can contribute to the development of dosage guideline for LLLT for treating MTrP-induced pain.

The fluence effects of low-level laser therapy on inflammation, fibroblast-like synoviocytes, and synovial apoptosis in rats with adjuvant-induced arthritis.

OBJECTIVE: The aim of this study was to evaluate the effect of low-level laser therapy (LLLT) operating at low and high fluences on joint inflammation, fibroblast-like synoviocytes (FLS), and synovial apoptosis in rats with adjuvant-induced arthritis. BACKGROUND DATA: Rheumatoid arthritis (RA) is characterized by pronounced inflammation and FLS proliferation within affected joints. Certain data indicate that LLLT is effective in patients with inflammation caused by RA; however, the fluence effects of LLLT on synovium are unclear. METHODS: Monoarthritis was induced in adult male Sprague-Dawley rats (250-300 g) via intraarticular injection of complete Freund's adjuvant (CFA) into the tibiotarsal joint. Animals were irradiated 72 h after CFA administration with a 780 nm GaAlAs laser at 4.5 J/cm2 (30 mW, 30 sec/spot) and 72 J/cm2 (80 mW, 180 sec/spot) daily for 10 days. After LLLT, the animals were euthanized and their arthritic ankles were collected for histopathological analysis, immunoassays of tumor necrosis factor (TNF)-α, matrix metallopeptidase (MMP)3 and 5B5, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays. RESULTS: LLLT at a fluence of 4.5 J/cm2 significantly reduced infiltration of inflammatory cells and expressions of TNF-α-, MMP3- and 5B5-like immunoreactivities, as well as resulting in more TUNEL-positive apoptotic cells in the synovium. No significant changes were observed in these biochemicals and inflammation in arthritic animals treated with 72 J/cm2. CONCLUSIONS: LLLT with low fluence is highly effective in reducing inflammation to sites of injury by decreasing the numbers of FLS, inflammatory cells, and mediators in the CFA-induced arthritic model. These data will be of value in designing clinical trials of LLLT for RA.

Low-level laser therapy alleviates neuropathic pain and promotes function recovery in rats with chronic constriction injury: possible involvements in hypoxia-inducible factor 1α (HIF-1α).

Nerve inflammation plays an important role in the development and progression of neuropathic pain after chronic constrictive injury (CCI). Recent studies have indicated that hypoxia-inducible factor 1α (HIF-1α) is crucial in inflammation. Low-level laser therapy has been used in treating musculoskeletal pain, but rare data directly support its use for neuropathic pain. We investigated the effects of low-level laser on the accumulation of HIF-1α, tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) in controlling neuropathic pain, as well as on the activation of vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) in promoting functional recovery in a rat CCI model. CCI was induced by placing four loose ligatures around the sciatic nerve of rats. Treatments of low-level laser (660 nm, 9 J/cm(2)) or sham irradiation (0 J/cm(2)) were performed at the CCI sites for 7 consecutive days. The effects of laser in animals with CCI were determined by measuring the mechanical paw withdrawal threshold, as well as the sciatic, tibial, and peroneal function indices. Histopathological and immunoassay analyses were also performed. Low-level laser therapy significantly improved paw withdrawal threshold and the sciatic, tibial, and peroneal functional indices after CCI. The therapy also significantly reduced the overexpressions of HIF-1α, TNF-α, and IL-1ß, and increased the amounts of VEGF, NGF, and S100 proteins. In conclusion, a low-level laser could modulate HIF-1α activity. Moreover, it may also be used as a novel and clinically applicable therapeutic approach for the improvement of tissue hypoxia/ischemia and inflammation in nerve entrapment neuropathy, as well as for the promotion of nerve regeneration. These findings might lead to a sufficient morphological and functional recovery of the peripheral nerve.

No synergistic effect of mesenchymal stem cells and exercise on functional recovery following sciatic nerve transection.

The present study examined whether transplantation of mesenchymal stem cells (MSCs) in combination with exercise would have synergistic effects leading to functional recovery that is greater than exercise alone. Sprague-Dawley rats received a sciatic nerve transection and were divided into four groups: denervated (control), denervated + exercise (control+Ex), denervated + MSC transplantation (MSC), and denervated + MSC transplantation + exercise (MSC+Ex). A volume of 1 x 105 of MSCs was injected into the lesion site in the MSC-treated groups, and culture medium in the control animals. Twelve hours after surgery, a swimming exercise regime was begun: 30 minutes/day for seven days in the MSC+Ex and control+Ex groups. Functional assessments including sciatic function index (SFI), vertical locomotor activity (VA), ankle activity (AA), and electrophysiological studies were performed to monitor the functional recovery. Histological analysis was performed to assess nerve continuity and myelination. No significant differences in SFI, VA, AA and electrophysiological studies were found between the MSC+Ex and control+Ex groups. Also, a morphological study revealed prominent axonal degeneration in the injured nerves of all animals. The results revealed that any synergistic effect of MSC transplantation on functional recovery of swimming exercise-treated transected nerve that may have existed was negligible.