Betulin Accelerated the Functional Recovery of Injured Muscle in a Mouse Model of Muscle Contusion.

Muscle contusion is an injury to muscle fibers and connective tissues. It commonly happens in impact events, and could result in pain, swelling, and limited range of motion. Diclofenac is one of commonly used nonsteroidal anti-inflammatory drugs to alleviate pain and inflammation after injury. However, it can potentially cause some side effects including gastrointestinal complications and allergy. Betulin is a lupine-type pentacyclic triterpenoid. It is showed to have valuable pharmacological effects, but the physiological effect of betulin on muscle contusion has not been reported. This study aimed to explore the therapeutic effects of betulin on muscle contusion that produced by the drop-mass method in mice. C57BL/6 mice were randomly assigned to control (no injury), only drop-mass injury (Injury), diclofenac treatment (Injury+diclofenac), and betulin treatment (Injury+betulin) groups. Injury was executed on the gastrocnemius of the right hind limb, and then phosphate-buffered saline (PBS), diclofenac, or betulin were oral gavage administrated respectively for 7 days. Results revealed that betulin significantly restored motor functions based on locomotor activity assessments, rota-rod test, and footprints analysis. Betulin also attenuated serum creatine kinase (CK) and lactate dehydrogenase (LDH) levels after muscle injury. Neutrophil infiltration was alleviated and desmin levels were increased after betulin treatment. Our data demonstrated that betulin attenuated muscle damage, alleviated inflammatory response, improved muscle regeneration, and restored motor functions after muscle contusion. Altogether, betulin may be a potential compound to accelerate the repair of injured muscle.

Does needle size matter? Effects of micro-hypodermic needle injections of botulinum toxin type A in patients with hemifacial spasm.

INTRODUCTION: Botulinum toxin type A (BoNT/A) injections are the first-line treatment for primary hemifacial spasms (HFS), but require frequent painful injections. Although micro-hypodermic needles are commonly used for aesthetic BoNT/A injections to lessen pain and bruising, their benefits in HFS remain unclear. OBJECTIVE: To compare side effects of BoNT/A injection, specifically pain and bruising, between primary HFS patients who received injections using micro-hypodermic needles (34-G) and those using standard needles (30-G). METHODS: This cross-over, double-blind, randomised controlled trial involved HFS patients who received BoNT/A injections using either a 34-G or 30-G needle at two visits 12 weeks apart. Primary outcomes, pain and bruising were assessed immediately after injection using the Visual Analogue Scale (VAS) and Short-form McGill Pain Questionnaire (Thai version, SF-MPQ). Bruise assessment was also conducted one week after each injection. Secondary outcomes involved comparing efficacy of BoNT/A between the two types of needles and assessing other complications beyond pain and bruising. RESULTS: 65 HFS patients (47 women and 18 men; mean age 59.46 ± 11.48 years; mean disease duration 5.86 ± 4.16 years) were included in the study. Patients who received 34-G needle injections reported significantly reduced pain, as indicated by VAS, total SF-MPQ scores, and bruise scores, compared to those who received 30-G needle injections (p < 0.001, each). There were no differences in efficacy or occurrence of other complications associated with BoNT/A between the two needle types. CONCLUSION: In HFS patients, BoNT/A injections using micro-hypodermic needles resulted in reduced pain and bruising, compared to standard needles, while maintaining similar BoNT/A benefits.

Rolipram-loaded PgP nanoparticle reduces secondary injury and enhances motor function recovery in a rat moderate contusion SCI model.

Spinal cord injury (SCI) results in immediate axonal damage and cell death, as well as a prolonged secondary injury consist of a cascade of pathophysiological processes. One important aspect of secondary injury is activation of phosphodiesterase 4 (PDE4) that leads to reduce cAMP levels in the injured spinal cord. We have developed an amphiphilic copolymer, poly (lactide-co-glycolide)-graft-polyethylenimine (PgP) that can deliver Rolipram, the PDE4 inhibitor. The objective of this work was to investigate the effect of rolipram loaded PgP (Rm-PgP) on secondary injury and motor functional recovery in a rat moderate contusion SCI model. We observed that Rm-PgP can increase cAMP level at the lesion site, and reduce secondary injury such as the inflammatory response by macrophages/microglia, astrogliosis by activated astrocytes and apoptosis as well as improve neuronal survival at 4 weeks post-injury (WPI). We also observed that Rm-PgP can improve motor functional recovery after SCI over 4 WPI.

Glibenclamide for Brain Contusions: Contextualizing a Promising Clinical Trial Design that Leverages an Imaging-Based TBI Endotype.

TBI heterogeneity is recognized as a major impediment to successful translation of therapies that could improve morbidity and mortality after injury. This heterogeneity exists on multiple levels including primary injury, secondary injury/host-response, and recovery. One widely accepted type of primary-injury related heterogeneity is pathoanatomic-the intracranial compartment that is predominantly affected, which can include any combination of subdural, subarachnoid, intraparenchymal, diffuse axonal, intraventricular and epidural hemorrhages. Intraparenchymal contusions carry the highest risk for progression. Contusion expansion is one of the most important drivers of death and disability after TBI. Over the past decade, there has been increasing evidence of the role of the sulfonylurea-receptor 1-transient receptor potential melastatin 4 (SUR1-TRPM4) channel in secondary injury after TBI, including progression of both cerebral edema and intraparenchymal hemorrhage. Inhibition of SUR1-TRPM4 with glibenclamide has shown promising results in preclinical models of contusional TBI with benefits against cerebral edema, secondary hemorrhage progression of the contusion, and improved functional outcome. Early-stage human research supports the key role of this pathway in contusion expansion and suggests a benefit with glibenclamide inhibition. ASTRAL is an ongoing international multi-center double blind multidose placebo-controlled phase-II clinical trial evaluating the safety and efficacy of an intravenous formulation of glibenclamide (BIIB093). ASTRAL is a unique and innovative study that addresses TBI heterogeneity by limiting enrollment to patients with the TBI pathoanatomic endotype of brain contusion and using contusion-expansion (a mechanistically linked secondary injury) as its primary outcome. Both criteria are consistent with the strong supporting preclinical and molecular data. In this narrative review, we contextualize the development and design of ASTRAL, including the need to address TBI heterogeneity, the scientific rationale underlying the focus on brain contusions and contusion-expansion, and the preclinical and clinical data supporting benefit of SUR1-TRPM4 inhibition in this specific endotype. Within this framework, we summarize the current study design of ASTRAL which is sponsored by Biogen and actively enrolling with a goal of 160 participants.

Morphofunctional Changes in the Spinal Cord of Rats after Contusion Injury with Local Delivery of Methylprednisolone in Combination with a Copolymer.

We studied the neuroprotective effect of local application of methylprednisolone in combination with a block copolymer after contusion spinal cord injury in rats. Histological analysis of the spinal cord showed that delivery of a complex of methylprednisolone with a block copolymer reduced the volume of white and gray matter lesions. An increase in the amplitude of the evoked response of the gastrocnemius muscle was observed during epidural stimulation of the spinal cord 6 h after the injury. The maximum amplitude of the muscle response was greater in the group with local delivery of the methylprednisolone complex with the polymer 72 h after the injury. The obtained results demonstrate the neuroprotective effect of the local administration of the complex and allow to make positive prognosis for the recovery of the sensorimotor functions in rats.

17beta-estradiol alleviates contusion-induced skeletal muscle injury by decreasing oxidative stress via SIRT1/PGC-1α/Nrf2 pathway.

PURPOSE: This study aimed to investigate the role of 17ß-estradiol (E2) in the repair of contusion-induced myoinjury in mice and to identify the underlying molecular mechanisms. METHODS: In vivo, contusion protocol was performed for preparing mice myoinjury model, and Injection (i.p.) of 17ß-estradiol (E2) or estrogen receptor antagonist ICI 182,780, or ovariectomy (OVX), was used to alter estrogen level of animal models. In vitro, C2C12 myoblasts were treated with H2O2 (oxidative stress inducer), SIRT1 inhibitor EX527, or aromatase inhibitor anastrozole. Serum E2 level was assessed by enzyme-linked immunosorbent assay (ELISA). Muscle damage repair was evaluated by H&E staining and the activities of serum creatine kinase (CK) and lactate dehydrogenase (LDH). The oxidative stress was estimated by the levels of catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA). Western blot was performed to measure the protein expressions of SIRT1, PGC-1α, Nrf2, and HO-1. RESULTS: We observed the elevated serum E2 levels and the upregulated oxidative stress in damaged muscle in female mice after contusion-induction. The E2 administration in vivo alleviated contusion-induced myoinjury in OVX mice by reducing CK and LDH activities, suppressing oxidative stress, and enhancing the expression levels of SIRT1, PGC-1α, Nrf2, and HO-1. These effects were inhibited by treatment with an ERα/ß antagonist. Moreover, EX527 or anastrozole treatment exacerbated H2O2-induced growth inhibition and oxidative stress, and expression downregulation of SIRT1, PGC-1α, Nrf2, and HO-1 in C2C12 cells in vitro. CONCLUSION: Our results suggest that E2 is a positive intervention factor for muscle repair followed contusion-induced myoinjury, through its effects on suppressing oxidative stress via activating the SIRT1/PGC-1α/Nrf2 pathway.

The effect of rutin on experimentally induced acute heart contusion in rats: Biochemical and histopathological evaluation.

BACKGROUND: Acute cardiac contusion induced by trauma is known with its high mortality and morbidity. The role of oxidative stress and inflammation in its pathophysiology has led to the investigation of antioxidant and anti-inflammatory substances in non-sur-gical treatment. In this study, the effects of rutin which has these two features on acute cardiac contusion were investigated. METHODS: Thirty male albino Wistar rats were divided into three equal groups as healthy (HG), contusion (CG), and rutin + con-tusion (rutin + CG). A heart contusion was created dropping 200 g weight from 1-m height onto anterior thorax of CG (n=10) and Rutin + CG (n=10) group animals by anesthetizing with intraperitoneal administration of 60 mg/kg ketamine and xylazine inhalation at appropriate intervals. Thirty minutes after contusion was applied, rutin at the dose of 50 mg/kg was administered orally to the stomach by gavage to the rutin + CG group animals. The rutin was used once a day for 2 days. Rats were killed at the end of 48 h. Heart tissues were removed and examined biochemically and histopathologically. Troponin I (TP I) and creatine kinase-MB (CK-MB) were measured in blood samples taken from the tail veins just before the rats were killed. RESULTS: TP I, CK-MB, malondialdehyde, total oxidant status, and nuclear factor-kappa B levels increased in the CG when compared to the HG, and Rutin application prevented this increase, total glutathione (eGSH) and total antioxidant status levels decreased, and rutin application prevented this decrease. Histopathological findings also supported these findings. CONCLUSION: Rutin had a protective effect on heart tissue.

Traditional processing, uses, phytochemistry, pharmacology and toxicology of Aconitum sinomontanum Nakai: A comprehensive review.

ETHNOPHARMACOLOGICAL RELEVANCE: As a folk medicine, Aconitum sinomontanum Nakai (Ranunculaceae) a perennial herbaceous flowering plant, is a widely used traditional Chinese medicine. Its rhizomes and roots are known as 'Gaowutou' in China, and it has been traditionally used for the treatment of rheumatoid arthritis, painful swelling of joints, bruises and injuries and has been known to grow well in regions of high altitude such as Gansu, Tibet etc. THE AIM OF THE REVIEW: This systematic review the comprehensive knowledge of the A. sinomontanum, including its traditional processing and uses, chemical constituents, pharmacological activities, toxicity assessment, pharmacokinetics and metabolism, and its use in clinical settings to emphasize the benefits of this species. We also discuss expectations for prospective research and implementation of this herb. This work lays a solid foundation for further development of A. sinomontanum. MATERIALS AND METHOD: Information on the studies of A. sinomontanum was collected from scientific journals, books, and reports via library and electronic data search (PubMed, Elsevier, Scopus, Google Scholar, Springer, Science Direct, Wiley, ACS, EMBASE, Web of Science and CNKI). Meanwhile, it was also obtained from published works of material medica, folk records, ethnopharmacological literatures, Ph.D. and Masters dissertation. RESULTS: As a member of the Ranunculaceae family, A. sinomontanum possesses its up-and-coming biological characteristics. It is widely reported for treating rheumatoid arthritis, painful swelling of joints, bruises and injuries. Currently, over 71 phytochemical ingredients have been obtained and identified from different parts of A. sinomontanum. Among them, alkaloids, flavonoids, steroids, glycosides are the major bioactive constituents. Activities such as antinociceptive, anti-inflammatory, antitumor, antiarrhythmic, local anesthetic, antipyretic, antimicrobial, insecticidal and others have been corroborated in vivo and in vitro. These properties are attributed to different alkaloids. In addition, many of the active ingredients, such as lappaconitine, ranaconitine and total alkaloids have been used as quality markers. CONCLUSION: This work contributes to update the ethnopharmacological uses, chemical constituents, pharmacological activities, toxicity assessment, pharmacokinetics and metabolism, and clinical settings information for A. sinomontanum, which provide basic information to help better understand the pharmacological and toxicological activities of A. sinomontanum in human. However, further in-depth studies are needed to determine the medical uses of this herb and its chemical constituents, pharmacological activities, clinical applications and toxicology.

Selenium Supplementation Alters IL-1ß and IL-6 Protein Levels in Contusion Model Rats.

<b>Background and Objective:</b> Contusion in skeletal muscles were common in athletes.Contusions usually occur when the tissue is exposed to a rapid and strong compressive force, for example, a direct blow, which usually results in the formation of a hematoma within the muscle. Contusion injuries impair the physiological function of the muscle. Supplementation is needed to shorten the healing process. Alternative therapy is antioxidant supplementation. Therefore, we conducted a study on the administration of the antioxidant selenium in contusion rats. <b>Materials and Methods:</b> The subject of this study were male Wistar rats. Rats were divided into 3 groups, namely control group, contusion group and selenium group. Each group consisted of 5 rats. Selenium dose was 0.0513 mg kg¹ b.wt., dissolved into 2% PGA given once a day, for 3 consecutive days. After treatment periods, CK-MM level, IL-1ß and IL-6 level were examined. <b>Results:</b> Protein expression of IL-1ß and IL-6 were significantly lower in the selenium treatment group compared to the contusion group. These results were confirmed by improved step gait in the selenium group. But there was no significant decrease in serum CK-MM levels expression in the selenium treatment group when compared to the contusion group. <b>Conclusion:</b> Selenium supplementation improved gait function after contusion by suppressing IL-1ß and IL-6 expression. However, selenium administration did not alter CK-MM levels.

Gyejibokryeong-Hwan improves recovery of injured muscles in mouse model of muscle contusion.

OBJECTIVE: To investigate the effects of Gyejibokryeong-Hwan (Guizhifuling-wan, GBH) on muscle injury in a mouse model of muscle contusion. METHODS: C57/BL6 mouse biceps femoris muscles were injured using the drop-mass method and injured animals were treated orally with GBH (50, 100, or 500 mg/kg) once a day for 7 d. Open field and treadmill running tests were performed to assess functional recovery from muscle injury. The production of pro-inflammatory cytokines was examined by enzyme-linked immunosorbent assay and Western blotting analysis. Expression of the muscle regeneration biomarkers, myoblast determination (MyoD), myogenic factor 5 (Myf5), and smooth muscle actin (α-SMA), in the biceps femoris muscle was investigated at the protein and mRNA level by Western blotting and real time-PCR, respectively. Histological analysis was performed using hematoxylin and eosin staining. Finally, myosin heavy chain production was investigated in differentiated C2C12 myoblasts in the presence of GBH. RESULTS: GBH treatment markedly improved locomotion and running behavior. GBH significantly inhibited the secretion of monocyte chemoattractant protein-1 into the bloodstream in muscle-contused animals. The levels of MyoD, Myf5, and α-SMA protein and mRNA were significantly up-regulated by GBH in injured muscle tissue. Histological studies suggested that GBH facilitated recovery from muscle damage. However, GBH did not induce the production of myosin heavy chain in vitro. CONCLUSION: Overall, the present study suggested that GBH improves the recovery of the injured muscles in the mouse model of muscle contusion.

Mediators of Prolonged Hematopoietic Progenitor Cell Mobilization After Severe Trauma.

BACKGROUND: This study investigated the molecular mediators of prolonged hematopoietic progenitor cell mobilization a trauma and chronic stress and the role of propranolol in modifying this response. METHODS: Sprague-Dawley rats were randomized to lung contusion (LC), LC plus hemorrhagic shock (LCHS), or LCHS with daily restraint stress (LCHS/CS). Propranolol was administered daily. Bone marrow (BM) and lung expression of high mobility group box 1 (HMGB1), granulocyte colony-stimulating factor (G-CSF), neutrophil elastase, stromal cell-derived factor 1 (SDF-1)/CXR4, and vascular cell adhesion protein 1 (VCAM-1)/very late antigen-4 were measured by real-time polymerase chain reaction. RESULTS: Bone marrow HMGB1, G-CSF, and neutrophil elastase expression were significantly elevated two- to four-fold after LCHS/CS, and all were decreased with the use of propranolol. SDF-1 and VCAM-1 were both significantly decreased after LCHS/CS. CONCLUSIONS: The increased expression of HMGB1 and G-CSF and decreased expression of BM anchoring molecules, SDF-1 and VCAM-1, after LCHS/CS, likely mediates prolonged hematopoietic progenitor cell mobilization. Propranolol's ability to reduce HMGB1, G-CSF, and neutrophil elastase expression suggests that the mobilization of hematopoietic progenitor cells was driven by persistent hypercatecholaminemia.

Oral non-steroidal anti-inflammatory drugs versus other oral analgesic agents for acute soft tissue injury.

BACKGROUND: Acute soft tissue injuries are common and costly. The best drug treatment for such injuries is not certain, although non-steroidal anti-inflammatory drugs (NSAIDs) are often recommended. There is concern about the use of oral opioids for acute pain leading to dependence. This is an update of a Cochrane Review published in 2015. OBJECTIVES: To assess the benefits or harms of NSAIDs compared with other oral analgesics for treating acute soft tissue injuries. SEARCH METHODS: We searched the CENTRAL, 2020 Issue 1, MEDLINE (from 1946), and Embase (from 1980) to January 2020; other databases were searched to February 2019. SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials involving people with acute soft tissue injury (sprain, strain, or contusion of a joint, ligament, tendon, or muscle occurring within 48 hours of inclusion in the study), and comparing oral NSAIDs versus paracetamol (acetaminophen), opioid, paracetamol plus opioid, or complementary and alternative medicine. The outcomes were pain, swelling, function, adverse effects, and early re-injury. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility, extracted data, and assessed risk of bias. We assessed the quality of the evidence using GRADE methodology. MAIN RESULTS: We included 20 studies, with 3305 participants. Three studies included children only. The others included predominantly young adults; approximately 60% were male. Seven studies recruited people with ankle sprains only. Most studies were at low or unclear risk of bias; however, two were at high risk of selection bias, three were at high risk of bias from lack of blinding, and five were at high risk of selective outcome reporting bias. Some evidence relating to pain relief was high certainty. Other evidence was either moderate, low or very low certainty, reflecting study limitations, indirectness, imprecision, or combinations of these. Thus, we are certain or moderately certain about some of the estimates, and uncertain or very uncertain of others. Eleven studies, involving 1853 participants compared NSAIDs with paracetamol. There were no differences between the two groups in pain at one to two hours (1178 participants, 6 studies; high-certainty evidence), at days one to three (1232 participants, 6 studies; high-certainty evidence), and at day seven or later (467 participants, 4 studies; low-certainty evidence). There was little difference between the groups in numbers of participants with minimal swelling at day seven or later (77 participants, 1 study; low-certainty evidence). Very low-certainty evidence from three studies (386 participants) means we are uncertain of the finding of little difference between the two groups in return to function at day seven or later. There was low-certainty evidence from 10 studies (1504 participants) that NSAIDs may slightly increase the risk of gastrointestinal adverse events compared with paracetamol. There was low-certainty evidence from nine studies (1679 participants) of little difference in neurological adverse events between the NSAID and paracetamol groups. Six studies, involving 1212 participants compared NSAIDs with opioids. There was moderate-certainty evidence of no difference between the groups in pain at one hour (1058 participants, 4 studies), and low-certainty evidence for no difference in pain at days four or seven (706 participants, 1 study). There was very low-certainty evidence of no important difference between the groups in swelling (84 participants, 1 study). Participants in the NSAIDs group were more likely to return to function in 7 to 10 days (542 participants, 2 studies; low-certainty evidence). There was moderate-certainty evidence (1143 participants, 5 studies) that NSAIDs were less likely to result in gastrointestinal or neurological adverse events compared with opioids. Four studies, involving 240 participants, compared NSAIDs with the combination of paracetamol and an opioid. The applicability of findings from these studies is in question because the dextropropoxyphene combination analgesic agents used are no longer in general use. Very low-certainty evidence means we are uncertain of the findings of no differences between the two interventions in the numbers with little or no pain at day one (51 participants, 1 study), day three (149 participants, 2 studies), or day seven (138 participants, 2 studies); swelling (230 participants, 3 studies); return to function at day seven (89 participants, 1 study); and the risk of gastrointestinal or neurological adverse events (141 participants, 3 studies). No studies reported re-injury rates. No studies compared NSAIDs with oral complementary and alternative medicines, AUTHORS' CONCLUSIONS: Compared with paracetamol, NSAIDs make no difference to pain at one to two hours and at two to three days, and may make no difference at day seven or beyond. NSAIDs may result in a small increase in gastrointestinal adverse events and may make no difference in neurological adverse events compared with paracetamol. Compared with opioids, NSAIDs probably make no difference to pain at one hour, and may make no difference at days four or seven. NSAIDs probably result in fewer gastrointestinal and neurological adverse effects compared with opioids. The very low-certainly evidence for all outcomes for the NSAIDs versus paracetamol with opioid combination analgesics means we are uncertain of the findings of no differences in pain or adverse effects. The current evidence should not be extrapolated to adults older than 65 years, as this group was not well represented in the studies.

The effects of selective beta-adrenergic blockade on bone marrow dysfunction following severe trauma and chronic stress.

INTRODUCTION: Propranolol has been shown to improve erythroid progenitor cell growth and anemia following trauma and this study sought to investigate the mechanisms involved by evaluating the effects of selective beta blockade. METHODS: Male Sprague-Dawley rats were subjected to lung contusion, hemorrhagic shock and chronic stress (LCHS/CS) ± daily selective beta-1, beta-2, or beta-3 blockade (B1B, B2B, B3B). Bone marrow cellularity and growth of erythroid progenitor colonies, hemoglobin, plasma granulocyte colony-stimulating factor (G-CSF), hematopoietic progenitor cell mobilization, and daily weight were assessed. RESULTS: Selective beta-2 and beta-3 blockade improved bone marrow cellularity, erythroid progenitor colony growth and hemoglobin levels, while decreasing plasma G-CSF, progenitor cell mobilization and weight loss following LCHS/CS. CONCLUSIONS: Attenuating the neuroendocrine stress response with the use of selective beta-2 and 3 adrenergic blockade may be an alternative to improve bone marrow erythroid function following trauma.

Developing a Topical Adjunct to Injectable Procedures.

Injectable procedures have come to play an enormous part in everyday aesthetic medical practice. Whether its use is directed at volumizing with fillers, decreasing volume using enzymes, skin-tightening using multi-needle approaches, or neuromuscular blockade, the injectable route is the means of delivery in all these cases, making injectable procedures the most common aesthetic procedure performed. As with all procedures, expected and unexpected consequences may follow including bruising, swelling, discomfort, and the possibility of infection. This paper outlines the scientific process and validation of a product designed as an adjunct to injection therapy and the scientific deep dive needed to encompass both symptomatic and adjunctive purposes. On the symptomatic side, bruising, swelling, and pain were considered, while volumetric enhancement, regeneration, and anti-microbial/biofilm effects were desired outcomes from the adjunctive perspective. Utilizing peptides and active agents aimed at reducing excess residual iron and stimulating macrophage absorption of red blood cells, we were able to achieve efficient resolution of bruising. In addition, peptides were included to stimulate collagen, elastin, and hyaluronic acid in synergy with the injectable. Anti-inflammatory, antimicrobial, and antibiofilm agents were added to aid in the safety profile of the injectable. In vivo testing of bruising resolution demonstrated that at day 2/3, participants using the study product (INhance Post-Injection Serum with TriHex Technology®, Alastin Skincare, Inc. Carlsbad, CA) had 73% less bruise color intensity and statistically significant improvement over the bland moisturizer. Overall, 81% of subjects applying the study topical product had less bruising at day 2/3 compared to the bland moisturizer. J Drugs Dermatol. 2020;19(4):398-404. doi:10.36849/JDD.2020.5016.

[Treatment of contusion of moderate severity in children in outpatient clinics]. / Lechenie detei s ushibom golovnogo mozga srednei stepeni tyazhesti v ambulatornykh usloviyakh.

OBJECTIVE: To determine the efficacy of cortexin in treatment of traumatic brain injuries with contusion of moderate severity in children in an outpatient clinics. MATERIALS AND METHODS: Seventy-four patients, aged 6-13 years, with a traumatic brain injury and a moderate brain contusion were examined. A comprehensive clinical examination, including neurological and ophthalmological examinations, EEG, brain CT scan, testing using a set of experimental psychological techniques, was performed. Children of the main group received standard therapy and cortexin. Children of the control group received similar treatment without cortexin. Re-examination was carried out 30 days after the start of treatment. RESULTS: After the treatment, a positive dynamics was noted in both groups. There were a decrease in the severity of subjective symptoms (p<0,01) and focal neurological symptoms (p <0,001) as well as absence of acute waves to physical activity according to EEG results in the main group compared with the control group. Also, EEG showed that cortical electrogenesis corresponded to the age of the patient, hypertensive/hydrocephalic signs were stopped (p <0,05), positive changes in cognitive functions occurred. CONCLUSION: The study showed the positive dynamics in the recovery of cognitive functions, the normalization of EEG parameters and stopping of hypertension-hydrocephalic symptoms in children with traumatic brain injuries with contusion of moderate severity a month after the start of treatment with cortexin.

Protective Effects of Resveratrol Supplementation on Contusion Induced Muscle Injury.

Muscle injuries frequently occur in contact sports events. The current treatment options for soft tissue injuries remain suboptimal and often result in delayed or incomplete recovery of damaged muscles. Resveratrol (RES) is a phenolic phytochemical, well-known for its antioxidant and anti-inflammatory properties. The purpose of this study is to evaluate the potential beneficial effects of RES supplementation on inflammation and regeneration in skeletal muscle after a contusion injury, in comparison to a conventional treatment of nonsteroidal anti-inflammatory drugs (NSAID). After one week of acclimation, forty eight -week-old male ICR mice were randomly divided into the five groups (n=8 per group): 1) normal control (NC), 2) mass-drop injury without any treatment (mass-drop injury, MDI), 3) post-injury NSAID treatment (MDI+ 10mg/kg NSAID), 4) post-injury RES supplementation (MDI+ 25mg/kg/day RES) and 5) post-injury treatment with RES and NSAID (MDI + resveratrol+ NSAID). After muscle contusion injury of the left gastrocnemius muscle, RES or NSAID were orally administered post-injury once a day for 7 days. Results showed that the MDI group had significantly higher serum uric acid (UA), CREA (creatinine), LDH (lactic dehydrogenase) and creatine kinase (CK) than the normal control group. Treatment with resveratrol reduced muscle damage as evidenced by the significantly decreased serum levels of UA, CREA, LDH and CK after contusion-induced muscle injuries in mice. In addition, RES and RES + NSAID groups promoted muscle satellite cell regeneration with increase in desmin protein after injury. Our results suggest that resveratrol combined with NSAID potentially improve muscle recovery and may be a potential candidate for further development as an effective clinical treatment for muscle repair.

Investigation of Bosentan's Effects on Pulmonary Contusion Created by Blunt Thoracic Trauma in Rats.

INTRODUCTION: Bosentan is an endothelin-1 receptor antagonist with anti-inflammatory, antioxidant, and antiproliferative effects. We aimed to evaluate its effects on lung tissue in a pulmonary contusion (PC) model. MATERIALS AND METHODS: The rats were randomly divided into five groups: PC3: PC evaluated on the 3rd day (n = 8), PC-B3: PC enteral bosentan 100 mg/kg/day, for 3 days (n = 8), PC7: PC evaluated on the 7th day (n = 7), PC-B7: PC 7 days bosentan 100 mg/kg/day, for 7 days (n = 8), C: control (n = 6). Unilateral lung contusion was created by dropping a metal weight onto the chest. The rats were sacrificed on the 3rd or the 7th days. The lung tissue was evaluated histopathologically for alveolar edema, congestion, and leukocyte infiltration, biochemically for malondialdehyde (MDA), superoxide dismutase (SOD), and nitric oxide (NO) levels, and immunohistochemically for inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), and apoptosis scores. RESULTS: Alveolar edema, congestion, and leukocyte infiltration scores were increased in all groups compared with the control group (p < 0.05) and decreased in bosentan-treated groups compared with the relevant nontreated groups (p < 0.05). Fibrosis was observed only in PC7 and PC-B7 groups. Bosentan did not have any effect on fibrosis development. iNOS and eNOS levels were higher in all groups compared with the control (p < 0.05) without a difference in the nontreated versus treated groups (p > 0.05). Bosentan treatment caused decreased MDA and increased SOD levels in comparison to the nontreated groups (p < 0.05). Tissue NO levels did not show any significant difference among groups. PC groups had higher levels of apoptosis compared with the control group (p < 0.05). The degree of apoptosis decreased in bosentan-treated groups compared with the nontreated groups (p < 0.05). CONCLUSION: PC causes progressive lung tissue damage. Bosentan reduced leukocyte infiltration and alveolar edema and congestion caused by PC. It also decreased MDA levels and increased SOD levels. Bosentan prevents tissue damage by inhibiting acute inflammatory response and reduces oxidative stress secondary to inflammation. It has therapeutic effects on apoptosis.

Melittin - A bee venom component - Enhances muscle regeneration factors expression in a mouse model of skeletal muscle contusion.

Melittin is a major peptide component of sweet bee venom that possesses anti-allergic, anti-inflammatory, anti-arthritis, anti-cancer, and neuroprotective properties. However, the therapeutic effects of melittin on muscle injury have not been elucidated. We investigated the therapeutic effects of melittin on muscle injury in a mouse model of muscle contusion. The biceps femoris muscle of the mice was injured using drop mass method, and the animals were treated with melittin (4, 20, or 100 µg/kg) for 7 days. Melittin significantly increased: locomotor activity in open field test, and treadmill running activity in a dose-dependent manner to level comparable to the positive control, diclofenac (30 mg/kg). Melittin treatment attenuated the pro-inflammatory cytokine MCP-1, TNF-α and IL-6. The expression of muscle regeneration biomarkers, including MyoD (muscle differentiation marker), myogenin, smooth muscle actin, and myosin heavy chain was markedly increased in the injured muscle tissue of melittin-treated mice, as determined by western blotting and quantitative real-time polymerase chain reaction. These results demonstrate that melittin inhibits inflammatory response and improves muscle damage by regenerating muscles in a mouse model of muscle contusion. Taken together, the results of present study suggest that melittin is a promising candidate for the muscle injury treatment.

Continuous infusion of an agonist of the tumor necrosis factor receptor 2 in the spinal cord improves recovery after traumatic contusive injury.

AIM: The activation of the TNFR2 receptor is beneficial in several pathologies of the central nervous system, and this study examines whether it can ameliorate the recovery process following spinal cord injury. METHODS: EHD2-sc-mTNFR2 , an agonist specific for TNFR2, was used to treat neurons exposed to high levels of glutamate in vitro. In vivo, it was infused directly to the spinal cord via osmotic pumps immediately after a contusion to the cord at the T9 level. Locomotion behavior was assessed for 6 weeks, and the tissue was analyzed (lesion size, RNA and protein expression, cell death) after injury. Somatosensory evoked potentials were also measured in response to hindlimb stimulation. RESULTS: The activation of TNFR2 protected neurons from glutamate-mediated excitotoxicity through the activation of phosphoinositide-3 kinase gamma in vitro and improved the locomotion of animals following spinal cord injury. The extent of the injury was not affected by infusing EHD2-sc-mTNFR2 , but higher levels of neurofilament H and 2', 3'-cyclic-nucleotide 3'-phosphodiesterase were observed 6 weeks after the injury. Finally, the activation of TNFR2 after injury increased the neural response recorded in the cortex following hindlimb stimulation. CONCLUSION: The activation of TNFR2 in the spinal cord following contusive injury leads to enhanced locomotion and better cortical responses to hindlimb stimulation.