losartan-potassium and Peripheral-Nerve-Injuries

Current strategies for promoting faster and more effective peripheral nerve healing have utilized a wide variety of techniques and approaches. Nerve grafts, conduits, and stem cell therapy all have their respective advantages. However, there are still some difficulties in attaining complete functional recovery with a single treatment modality. The utilization of adjuvant treatments, in combination with current standard-of-care methods, offers the potential to improve patient outcomes. This paper highlights the current landscape of adjuvant treatments for enhancing peripheral nerve repair and regeneration.

Topics: Absorbable Implants; Allografts; Autografts; Calcium Channel Blockers; Erythropoietin; Gabapentin; Humans; Immunosuppressive Agents; Lithium Compounds; Nerve Regeneration; Neuroprotective Agents; Neurosurgical Procedures; Peripheral Nerve Injuries; Peripheral Nerves; Recovery of Function; Riluzole; Stem Cell Transplantation; Valproic Acid; Veins; Wallerian Degeneration

Advances in the neurobiology of growth factors, neural development, and prevention of cell death have resulted in a heightened clinical interest for the development of protective and regenerative neuromodulatory strategies for the cavernous nerves (CNs), as therapies for prostate cancer and other pelvic malignancies often result in neuronal damage and debilitating loss of sexual function. Nitric oxide released from the axonal end plates of these nerves within the corpora cavernosa causes relaxation of smooth muscle, initiating the haemodynamic changes of penile erection as well as contributing to maintained tumescence; the loss of CN function is primarily responsible for the development of erectile dysfunction (ED) after pelvic surgery and serves as the primary target for potential neuroprotective or regenerative strategies. Evidence from pre-clinical studies for select neuromodulatory approaches is reviewed, including neurotrophins, glial cell line-derived neurotrophic factors (GDNF), bone morphogenic proteins, immunophilin ligands, erythropoetin (EPO), and stem cells.

Topics: Animals; Bone Morphogenetic Proteins; Brain-Derived Neurotrophic Factor; Erectile Dysfunction; Erythropoietin; Glial Cell Line-Derived Neurotrophic Factor; Growth Differentiation Factor 5; Humans; Immunophilins; Male; Nerve Growth Factors; Neurotransmitter Agents; Penis; Peripheral Nerve Injuries; Postoperative Complications; Stem Cell Transplantation

Erythropoietin has neuroregenerative effects. Fibrin glue may be used for nerve repair and controlled release of substances. In this study, the authors investigated the effects of erythropoietin-containing fibrin glue on nerve repair, based on the hypothesis that erythropoietin-containing fibrin glue would positively affect nerve regeneration.. Thirty-six Long-Evans rats were used. The animals were divided into six groups. Their left sciatic nerves were isolated, transected, and repaired with saline-containing fibrin glue in group 1, with erythropoietin-containing fibrin glue in group 2, with saline-containing fibrin glue and two sutures in group 3, with erythropoietin-containing fibrin glue and two sutures in group 4, with two sutures in group 5, and with four sutures in group 6. Sciatic Functional Index calculation, pin-prick test, and toe-spread test were performed on days 21, 42, and 63. All animals were killed on day 63. The nerve sections were analyzed histologically.. The Sciatic Functional Index, pin-prick test, and toe-spread test results were the best in group 4 and the worst in group 5. Group 4 showed superior Schwann cell proliferation (p < 0.05). Groups with epineural suture use (groups 3, 4, 5, and 6) had higher endoneurial collagen synthesis scores than the groups without suture use (groups 1 and 2) (p < 0.05). The myelin protein zero immunostaining results were significantly higher in the erythropoietin-treated groups (groups 2 and 4) (p < 0.05).. The combined use of erythropoietin-containing fibrin glue and two epineural sutures (group 4) showed a statistically significant improvement in many parameters.. Fibrin glue is already used in nerve repair. Adding erythropoietin to fibrin glue could be a safe and easy option to improve nerve regeneration.

Topics: Animals; Disease Models, Animal; Erythropoietin; Fibrin Tissue Adhesive; Nerve Regeneration; Peripheral Nerve Injuries; Rats; Rats, Long-Evans; Sciatic Nerve

We aimed to investigate the effects of erythropoietin, acetyl-l-carnitine, and their combination on nerve regeneration in experimental peripheral nerve injury.. Rats were randomly divided into five groups - sham-operated (S), sciatic nerve crush injury (C), C + acetyl-l-carnitine (ALCAR), C + erythropoietin (EPO), and C + EPO + ALCAR. ALCAR (50 mg/kg/day) was administered intraperitoneally, and EPO (5000 U/kg) was injected subcutaneously for 10 days. Functional recovery was evaluated using walking track analysis (sciatic functional index [SFI]), somatosensory evoked potentials (SEPs), thiobarbituric acid reactive substance (TBARS) assay, and caspase-3 and S100 immunoreactivities.. In SFI analyses, delayed functional recovery was observed in the C group, whereas the functional recovery of rats treated with EPO and ALCAR significantly improved. The latencies of the SEP components were significantly prolonged in C group. In the treatment groups (C + EPO, C + ALCAR, and C + EPO + ALCAR), all recorded values of SEP components significantly decreased. TBARS levels in C group were significantly higher than those in the S group. EPO and ALCAR administration significantly decreased TBARS levels. Caspase-3 immunoreactivity was increased in the C group, whereas it was decreased in the treatment groups. S100 immunolabelling was significantly decreased in the C group. EPO and ALCAR administration caused an increase in the amount of S100-positive cells in all treatment groups.. EPO and ALCAR administration could accelerate sciatic nerve repair by reducing apoptosis and lipid peroxidation and promoting myelinization. Although both EPO and ALCAR had positive effects on nerve healing, their combined efficacy had no statistically significant effect on peripheral nerve regeneration.

Topics: Acetylcarnitine; Animals; Caspase 3; Erythropoietin; Nerve Regeneration; Peripheral Nerve Injuries; Rats; Sciatic Nerve; Sciatic Neuropathy; Thiobarbituric Acid Reactive Substances

Topics: Erythropoietin; Humans; Macrophages; Peripheral Nerve Injuries; Phagocytosis; Schwann Cells

Traumatic peripheral nerve injury (TPNI) is a major medical problem with no universally accepted pharmacologic treatment. We hypothesized that encapsulation of pro-angiogenic erythropoietin (EPO) in amphiphilic PLGA-PEG block copolymers could serve as a local controlled-release drug delivery system to enhance neurovascular regeneration after nerve injury.. In this study, we synthesized an EPO-PLGA-PEG block copolymer formulation. We characterized its physiochemical and release properties and examined its effects on functional recovery, neural regeneration, and blood vessel formation after sciatic nerve crush injury in mice.. EPO-PLGA-PEG underwent solution-to-gel transition within the physiologically relevant temperature window and released stable EPO for up to 18 days. EPO-PLGA-PEG significantly enhanced sciatic function index (SFI), grip strength, and withdrawal reflex post-sciatic nerve crush injury. Furthermore, EPO-PLGA-PEG significantly increased blood vessel density, number of junctions, and myelinated nerve fibers after injury.. This study provides promising preclinical evidence for using EPO-PLGA-PEG as a local controlled-release treatment to enhance functional outcomes and neurovascular regeneration in TPNI.

Topics: Animals; Crush Injuries; Delayed-Action Preparations; Erythropoietin; Mice; Nerve Regeneration; Peripheral Nerve Injuries; Sciatic Neuropathy

Erythropoietin (EPO) promotes myelination and functional recovery in rodent peripheral nerve injury (PNI). While EPO receptors (EpoR) are present in Schwann cells, the role of EpoR in PNI recovery is unknown because of the lack of EpoR antagonists or Schwann cell-specific EpoR knockout animals.. Using the Cre-loxP system, we developed a myelin protein zero (Mpz) promoter-driven knockout mouse model of Schwann cell EpoR (MpzCre-EpoR. EPO treatment significantly accelerated functional recovery in control mice in contrast to significantly reduced functional recovery in Mpz-EpoR-KO mice. Significant muscle atrophy was found in the injured hindlimb of EPO-treated Mpz-EpoR-KO mice but not in EPO-treated control mice.. These preliminary findings provide direct evidence for an obligatory role of Schwann-cell specific EpoR for EPO-induced functional recovery and muscle atrophy following PNI.

Topics: Animals; Crush Injuries; Erythropoietin; Mice; Mice, Knockout; Muscular Atrophy; Peripheral Nerve Injuries; Receptors, Erythropoietin; Recovery of Function; Reverse Transcriptase Polymerase Chain Reaction; Schwann Cells; Sciatic Nerve

We aimed to investigate the effects of umbilical cord-derived mesenchymal stem cells and erythropoietin on nerve regeneration in the sciatic nerve 'crush injury' in a rat model.. Experimental animals were randomly divided into 5 groups: Crush Injury, Sham, Crush Injury + Erythropoietin, Crush Injury + Mesenchymal Stem Cell, Crush Injury + Erythropoietin + Mesenchymal Stem Cell groups. Crush injury made with bulldog clamp. Mesencyhmal stem cells delivered by enjection locally. Erythropoietin administered by intraperitoneally. On the 0th, 14th and 28th days, all groups underwent a sciatic functional index test. On 28th day, sciatic nerves were harvested and histopathological appearance, axon number and axon diameter of the sciatic nerves were evaluated with Oil Red O staining. Immunoreactivity of nerve growth factor, neurofilament-H and caspase-3 were determined by immunofluorescence staining in nerve tissue.. In histopathological examination, axons and nerve bundles exhibiting normal nerve architecture in the Sham group. Crush Injury + Mesenchymal Stem Cell group has similar histological appearance to the Sham group. The number of axons were higher in the Mesenchymal Stem Cell groups compared to the Crush Injury group. Nerve growth factor immunoreactivity intensity was significantly lower in Crush Injury + Mesenchymal Stem Cell group compared to Crush Injury group. Neurofilament-H density was higher in the treatment groups when compared to the Crush Injury group.. In this study, it was found that umbilical cord-derived mesenchymal stem cells and erythropoietin treatments effects positively regeneration of crush injury caused by bulldog clamp in the sciatic nerve of rats.

Topics: Animals; Cord Blood Stem Cell Transplantation; Crush Injuries; Erythropoietin; Female; Mesenchymal Stem Cell Transplantation; Nerve Regeneration; Peripheral Nerve Injuries; Random Allocation; Rats; Rats, Wistar; Sciatic Nerve

Peripheral nerve injury (PNI) often leads to significant functional loss in patients and poses a challenge to physicians since treatment options for improving functional outcomes are limited. Recent studies suggest that erythropoietin and glucocoticoids have beneficial effects as mediators of neuro-regenerative processes. We hypothesized that combination treatment with erythropoietin and glucocoticoids would have a synergistic effect on functional outcome after PNI.. Sciatic nerve crush injury was simulated in ten-week-old male C57BL/6 mice. The mice were divided into four groups according to the type of drugs administered (control, erythropoietin, dexamethasone, and erythropoietin with dexamethasone). Motor functional recovery was monitored by walking track analysis at serial time points up to 28 days after injury. Morphological analysis of the nerve was performed by immunofluorescent staining for neurofilament (NF) heavy chain and myelin protein zero (P0) in cross-sectional and whole-mount nerve preparations. Additionally, morphological analysis of the muscle was performed by Hematoxylin and eosin staining.. Combination treatment with erythropoietin and dexamethasone significantly improved the sciatic functional index at 3, 7, 14, and 28 days after injury. Fluorescence microscopy of cross sectional nerve revealed that the combination treatment increased the ratio of P0/NF-expressing axons. Furthermore, confocal microscopy of the whole-mount nerve revealed that the combination treatment increased the fluorescence intensity of P0 expression. The cross-sectional area and minimum Feret's diameter of the muscle fibers were significantly larger in the mice which received combination treatment than those in the controls.. Our results demonstrated that combination treatment with erythropoietin and dexamethasone accelerates functional recovery and reduces neurogenic muscle atrophy caused by PNI in mice, which may be attributed to the preservation of myelin and Schwann cell re-myelination. These findings may provide practical therapeutic options for patients with acute PNI.

Topics: Acute Disease; Animals; Axons; Dexamethasone; Disease Models, Animal; Drug Therapy, Combination; Erythropoietin; Male; Mice; Mice, Inbred C57BL; Microscopy, Confocal; Muscles; Muscular Atrophy; Myelin P0 Protein; Peripheral Nerve Injuries; Recovery of Function; Remyelination; Schwann Cells; Sciatic Nerve

The reported prognosis for recovery after peripheral nerve injury is remarkably poor. Deficits may persist for years, resulting in significant functional disability. Both corticosteroids and Erythropoietin have been investigated as neuroprotective agents; however, their efficacy in total hip and knee arthroplasty is not known. The purpose of this study was to evaluate the effect of systemically-administered Erythropoietin and tapered oral corticosteroids on the recovery of postoperative nerve palsies in the setting of total hip and knee arthroplasty.. Eleven patients sustaining postoperative peripheral nerve injuries after total hip or knee arthroplasty were treated acutely with Erythropoietin and tapered oral steroids. Motor and sensory function was assessed clinically pre- and postoperatively until complete motor recovery or for a minimum of 1 year.. Motor loss was complete in seven (64%) patients and partial in four (36%). Seven (64%) patients' symptoms affected the common peroneal nerve distribution and four (36%) had concomitant tibial nerve involvement. Eight (73%) patients experienced full motor recovery at an average of 39 days (range: 3-133 days), and three (27%) had near-complete motor recovery. At final follow up, no patient required assistive devices for ambulation.. Administration of Erythropoietin coupled with oral tapered steroids for patients sustaining iatrogenic nerve injuries in total hip and knee arthroplasty demonstrated faster and more complete recovery of motor and sensory function compared to previous reports in the literature. This study highlights the importance of further investigation to define the role of each in the setting of acute postoperative nerve palsies.. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Topics: Adrenal Cortex Hormones; Adult; Aged; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Erythropoietin; Female; Humans; Iatrogenic Disease; Intraoperative Complications; Male; Middle Aged; Peripheral Nerve Injuries; Prognosis; Recovery of Function; Retrospective Studies; Risk Factors; United States

Erythropoietin (EPO) has been demonstrated to exert neuroprotective effects on peripheral nerve injury recovery. Though daily intraperitoneal injection of EPO during a long period of time was effective, it was a tedious procedure. In addition, only limited amount of EPO could reach the injury sites by general administration, and free EPO is easily degraded in vivo. In this study, we encapsulated EPO in poly(lactide-co-glycolide) (PLGA) microspheres. Both in vitro and in vivo release assays showed that the EPO-PLGA microspheres allowed sustained release of EPO within a period of two weeks. After administration of such EPO-PLGA microspheres, the peripheral nerve injured rats had significantly better recovery compared with those which received daily intraperitoneal injection of EPO, empty PLGA microspheres, or saline treatments. This was supported by the functional, electrophysiological, and histological evaluations of the recovery done at week 8 postoperatively. We conclude that sustained delivery of EPO could be achieved by using EPO-PLGA microspheres, and such delivery method could further enhance the recovery function of EPO in nerve injury recovery.

Topics: Animals; Capsules; Delayed-Action Preparations; Diffusion; Erythropoietin; Lactic Acid; Male; Nerve Regeneration; Neuroprotective Agents; Peripheral Nerve Injuries; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rats; Rats, Sprague-Dawley; Recovery of Function; Treatment Outcome

In the present study, the effects of erythropoietin (EPO) on preventing adult neurons from apoptosis (introduced by brachial plexus avulsion) were examined, and the mechanism was analyzed. Fifty injury rat models were established in this study by using micro-hemostat forceps to pull out brachial plexus root from the intervertebral foramen in supine position. These models were divided into EPO group (avulsion + 1000 U/kg subcutaneously on alternate days) and control group (avulsion + normal saline). C5-T1 spinal cord was harvested at days 1, 2, 4, 7, and 14. Compared with the control group, the apoptosis of spinal motoneurons was significantly decreased on days 4 and 7 in the EPO group, which was also approved by TUNEL examination results. The detection of p-JNK and expression of c-Jun and cleavage of cleaved PARP (c-PARP) were also examined by immunohistochemistry and were increased immediately at day 1, and peaked at day 2, day 2, and day 4 in control group, respectively. However, the amounts were decreased and delayed by EPO treatment significantly at the same time points. In conclusion, the apoptosis of adult spinal motorneurons was associated with JNK phosphorylation, c-Jun expression, and caspase activity, and EPO-mediated neuronal protective effect is proved by downregulating the JNK phosphorylation and c-Jun expression and inhibiting of c-PARP cleavage.

Topics: Animals; Apoptosis; Brachial Plexus; Down-Regulation; Erythropoietin; JNK Mitogen-Activated Protein Kinases; Male; MAP Kinase Kinase 4; MAP Kinase Signaling System; Neurons; Peripheral Nerve Injuries; Poly(ADP-ribose) Polymerases; Proteolysis; Rats; Rats, Wistar

Erythropoietin (EPO) is a pleiotropic cytokine with neuroprotective, anti-inflammatory, and muscle regenerative properties. The purpose of our study was to analyze the regenerative capacity of systemically applied EPO in a combined muscle-nerve injury model.. We performed a crush injury to the left soleus muscle in 84 male Wistar rats. Using an instrumented clamp, the muscle was crushed over its complete length. Simultaneously, the ipsilateral sciatic nerve was sham manipulated or crushed. Upon induction of the trauma, animals received either EPO (E) (single application of 5,000 IU/kg body weight intraperitonial) or vehicle solution (K). After in vivo assessment of mechanical pain according to Frey, thermal hyperalgesia, latency of nerve conduction velocity, and strength of the soleus muscle were analyzed at days 1, 7, and 42 postinjury (n = 7 per group). Cell proliferation and apoptosis were assessed by means of histology and immunohistochemistry.. Combined muscle-nerve injury showed a significant loss of muscle strength, which incompletely recovered within 42 days. Rats treated with EPO showed an increased muscle strength after 7 days and 42 days compared with the control group. Pain behavior was highest in the muscle-nerve injured animals at day 7. EPO decreased the pain and increased nerve conduction velocity. Nerve injury diminished proliferation of muscle cells, whereas simultaneous therapy with EPO resulted in a boost of bromdesoxyuridine-positive cells.. EPO promoted muscle restoration and enhanced nerve recovery after combined muscle-nerve injury. Thus, EPO might represent an attractive therapeutic option to optimize the posttraumatic course after injury.

Topics: Animals; Crush Syndrome; Disease Models, Animal; Erythropoietin; Hindlimb; Immunohistochemistry; Injections, Intraperitoneal; Male; Muscle Strength; Muscle, Skeletal; Nerve Regeneration; Neural Conduction; Peripheral Nerve Injuries; Random Allocation; Rats; Rats, Wistar; Reference Values; Regeneration; Sciatic Nerve; Sensitivity and Specificity

The aim of the present study is to evaluate the effects of erythropoietin to the collateral sprouting by using systemically delivered erythropoietin in an end-to-side nerve repair model. Forty-five rats were evaluated in four groups: (A) end-to-side neurorrhaphy only, (B) end-to-side neurorrhaphy and erythropoietin administration, (C) end-to-end neurorrhaphy and (D) nerve stumps buried into neighboring muscles. In all animals, the contralateral healthy side served as control. Functional assessment of nerve regeneration was performed at intervals up to 5 months using the Peroneal Function Index. Evaluation 150 days after surgery included peroneal and tibial nerve morphometric examination, and wet weights of the tibialis anterior muscle. During the first three weeks after surgery, when erythropoietin was regularly administered, functional evaluation showed that erythropoietin may facilitate peripheral nerve regeneration. However, there was rapid deterioration in the functional recovery when erythropoietin's administration was discontinued. As a consequence, at the end of this study, erythropoietin failed to maintain its initial stimulating effect in axonal regeneration. The results of wet muscle weights revealed statistically significant differences between Groups A and C, and Group B. Furthermore, data on axonal counting showed significant difference between Groups A and C, and Group B. Erythropoietin appears to facilitate peripheral nerve regeneration at the initial phase of its administration. Further investigation will be necessary to optimise the conditions (dose, mode of administration) in order to maintain its effects.

Topics: Animals; Denervation; Erythropoietin; Ganglia, Spinal; Growth Cones; Male; Motor Neurons; Muscle, Skeletal; Nerve Growth Factors; Nerve Regeneration; Neurons, Afferent; Neurosurgical Procedures; Organ Size; Peripheral Nerve Injuries; Peripheral Nerves; Peroneal Nerve; Rats; Rats, Wistar; Recovery of Function; Tibial Nerve; Treatment Outcome; Withholding Treatment

Erythropoietin (Epo) expresses potent neuroprotective activity in the peripheral nervous system; however, the underlying mechanism remains incompletely understood. In this study, we demonstrate that Epo is upregulated in sciatic nerve after chronic constriction injury (CCI) and crush injury in rats, largely due to local Schwann cell production. In uninjured and injured nerves, Schwann cells also express Epo receptor (EpoR), and its expression is increased during Wallerian degeneration. CCI increased the number of Schwann cells at the injury site and the number was further increased by exogenously administered recombinant human Epo (rhEpo). To explore the activity of Epo in Schwann cells, primary cultures were established. These cells expressed cell-surface Epo receptors, with masses of 71 and 62 kDa, as determined by surface protein biotinylation and affinity precipitation. The 71-kDa species was rapidly but transiently tyrosine-phosphorylated in response to rhEpo. ERK/MAP kinase was also activated in rhEpo-treated Schwann cells; this response was blocked by pharmacologic antagonism of JAK-2. RhEpo promoted Schwann cell proliferation, as determined by BrdU incorporation. Cell proliferation was ERK/MAP kinase-dependent. These results support a model in which Schwann cells are a major target for Epo in injured peripheral nerves, perhaps within the context of an autocrine signaling pathway. EpoR-induced cell signaling and Schwann cell proliferation may protect injured peripheral nerves and promote regeneration.

Topics: Animals; Autocrine Communication; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Erythropoietin; Extracellular Signal-Regulated MAP Kinases; Female; Janus Kinase 2; Male; Nerve Regeneration; Peripheral Nerve Injuries; Peripheral Nerves; Phosphorylation; Protein Isoforms; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Rats; Rats, Sprague-Dawley; Receptors, Erythropoietin; Recombinant Proteins; RNA, Messenger; Schwann Cells; Sciatic Neuropathy; Up-Regulation