Prostate cancer is the second most common malignancy and the sixth leading cause of cancer-related death in men worldwide. Radical prostatectomy (RP) is the standard treatment for localized prostate cancer, but the procedure often results in postoperative erectile dysfunction (ED). The poor efficacy of phosphodiesterase 5 inhibitors after surgery highlights the need to develop new therapies to enhance cavernous nerve regeneration and improve the erectile function of these patients. In the present study, we aimed to examine the potential of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in preserving erectile function in cavernous nerve injury (CNI) mice. We found that HB-EGF expression was reduced significantly on the 1 st day after CNI in penile tissue. Ex vivo and in vitro studies showed that HB-EGF promotes major pelvic ganglion neurite sprouting and neuro-2a (N2a) cell migration. In vivo studies showed that exogenous HB-EGF treatment significantly restored the erectile function of CNI mice to 86.9% of sham levels. Immunofluorescence staining showed that mural and neuronal cells were preserved by inducing cell proliferation and reducing apoptosis and reactive oxygen species production. Western blot analysis showed that HB-EGF upregulated protein kinase B and extracellular signal-regulated kinase activation and neurotrophic factor expression. Overall, HB-EGF is a major promising therapeutic agent for treating ED in postoperative RP.
Animals ; Male ; Heparin-binding EGF-like Growth Factor/therapeutic use* ; Erectile Dysfunction/etiology* ; Mice ; Penis/drug effects* ; Nerve Regeneration/drug effects* ; Penile Erection/drug effects* ; Peripheral Nerve Injuries/drug therapy* ; Cell Proliferation/drug effects* ; Apoptosis/drug effects* ; Cell Movement/drug effects* ; Prostatectomy/adverse effects* ; Mice, Inbred C57BL ; Reactive Oxygen Species/metabolism*

Patients suffering from nerve injury often experience exacerbated pain responses and complain of memory deficits. The dorsal hippocampus (dHPC), a well-defined region responsible for learning and memory, displays maladaptive plasticity upon injury, which is assumed to underlie pain hypersensitivity and cognitive deficits. However, much attention has thus far been paid to intracellular mechanisms of plasticity rather than extracellular alterations that might trigger and facilitate intracellular changes. Emerging evidence has shown that nerve injury alters the microarchitecture of the extracellular matrix (ECM) and decreases ECM rigidity in the dHPC. Despite this, it remains elusive which element of the ECM in the dHPC is affected and how it contributes to neuropathic pain and comorbid cognitive deficits. Laminin, a key element of the ECM, consists of α-, β-, and γ-chains and has been implicated in several pathophysiological processes. Here, we showed that peripheral nerve injury downregulates laminin β1 (LAMB1) in the dHPC. Silencing of hippocampal LAMB1 exacerbates pain sensitivity and induces cognitive dysfunction. Further mechanistic analysis revealed that loss of hippocampal LAMB1 causes dysregulated Src/NR2A signaling cascades via interaction with integrin β1, leading to decreased Ca²⁺ levels in pyramidal neurons, which in turn orchestrates structural and functional plasticity and eventually results in exaggerated pain responses and cognitive deficits. In this study, we shed new light on the functional capability of hippocampal ECM LAMB1 in the modulation of neuropathic pain and comorbid cognitive deficits, and reveal a mechanism that conveys extracellular alterations to intracellular plasticity. Moreover, we identified hippocampal LAMB1/integrin β1 signaling as a potential therapeutic target for the treatment of neuropathic pain and related memory loss.
Animals ; Laminin/genetics* ; Hippocampus/metabolism* ; Neuralgia/metabolism* ; Cognitive Dysfunction/etiology* ; Male ; Peripheral Nerve Injuries/metabolism* ; Extracellular Matrix/metabolism* ; Integrin beta1/metabolism* ; Pyramidal Cells/metabolism* ; Signal Transduction

Humans ; Sciatic Neuropathy/etiology* ; Arthroplasty, Replacement, Hip/adverse effects* ; Peripheral Nerve Injuries/etiology* ; Sciatic Nerve/injuries*

Neuropathic pain is a chronic debilitating symptom characterized by spontaneous pain and mechanical allodynia. It occurs in distinct forms, including brush-evoked dynamic and filament-evoked punctate mechanical allodynia. Potassium channel 2.1 (Kir2.1), which exhibits strong inward rectification, is and regulates the activity of lamina I projection neurons. However, the relationship between Kir2.1 channels and mechanical allodynia is still unclear. In this study, we first found that pretreatment with ML133, a selective Kir2.1 inhibitor, by intrathecal administration, preferentially inhibited dynamic, but not punctate, allodynia in mice with spared nerve injury (SNI). Intrathecal injection of low doses of strychnine, a glycine receptor inhibitor, selectively induced dynamic, but not punctate allodynia, not only in naïve but also in ML133-pretreated mice. In contrast, bicuculline, a GABA receptor antagonist, induced only punctate, but not dynamic, allodynia. These results indicated the involvement of glycinergic transmission in the development of dynamic allodynia. We further found that SNI significantly suppressed the frequency, but not the amplitude, of the glycinergic spontaneous inhibitory postsynaptic currents (gly-sIPSCs) in neurons on the lamina II-III border of the spinal dorsal horn, and pretreatment with ML133 prevented the SNI-induced gly-sIPSC reduction. Furthermore, 5 days after SNI, ML133, either by intrathecal administration or acute bath perfusion, and strychnine sensitively reversed the SNI-induced dynamic, but not punctate, allodynia and the gly-sIPSC reduction in lamina IIi neurons, respectively. In conclusion, our results suggest that blockade of Kir2.1 channels in the spinal dorsal horn selectively inhibits dynamic, but not punctate, mechanical allodynia by enhancing glycinergic inhibitory transmission.
Animals ; Bicuculline ; pharmacology ; Disease Models, Animal ; Glycine ; metabolism ; Hyperalgesia ; drug therapy ; etiology ; metabolism ; Imidazoles ; pharmacology ; Inhibitory Postsynaptic Potentials ; drug effects ; physiology ; Male ; Mice, Inbred C57BL ; Neurons ; drug effects ; metabolism ; Neurotransmitter Agents ; pharmacology ; Peripheral Nerve Injuries ; drug therapy ; metabolism ; Phenanthrolines ; pharmacology ; Potassium Channels, Inwardly Rectifying ; antagonists & inhibitors ; metabolism ; Receptors, GABA-A ; metabolism ; Receptors, Glycine ; metabolism ; Strychnine ; pharmacology ; Synaptic Transmission ; drug effects ; physiology ; Tissue Culture Techniques ; Touch

We evaluated whether LIM-kinase 2 inhibitor (LIMK2i) could improve erectile function by suppressing corporal fibrosis through the normalization of the Rho-associated coiled-coil protein kinase 1 (ROCK1)/LIMK2/Cofilin pathway in a rat model of cavernous nerve crush injury (CNCI). Sixty 11-week-old male Sprague-Dawley rats were divided equally into five groups: sham surgery (S), CNCI (I), and CNCI treated with low-dose (L), medium-dose (M), and high-dose (H) LIMK2i. The L, M, and H groups were treated with a daily intraperitoneal injection of LIMK2i (2.5, 5.0, and 10.0 mg kg^-1 body weight, respectively) for 1 week after surgery. The erectile response was assessed using electrostimulation at 1 week, postoperatively. Penile tissues were processed for Masson's trichrome staining, double immunofluorescence, and Western blot assay. Erectile responses in the H group improved compared with the I group, while the M group showed only partial improvement. A significantly decreased smooth muscle/collagen ratio and an increased content of fibroblasts positive for phospho-LIMK2 were noted in the I group. The M and H groups revealed significant improvements in histological alterations and the dysregulated LIMK2/Cofilin pathway, except for LIMK2 phosphorylation in the M group. The inhibition of LIMK2 did not affect the ROCK1 protein expression. The content of fibroblasts positive for phospho-LIMK2 in the H group returned to the level found in the S group, whereas it did not in the M group. However, the L group did not exhibit such improvements. Our data suggest that the inhibition of LIMK2, particularly with administration of 10.0 mg kg^-1 body weight LIMK2i, can improve corporal fibrosis and erectile function by normalizing the LIMK2/Cofilin pathway.
Animals ; Cofilin 1/metabolism* ; Electric Stimulation ; Erectile Dysfunction/etiology* ; Fibroblasts/pathology* ; Fibrosis/drug therapy* ; Lim Kinases/antagonists & inhibitors* ; Male ; Penile Diseases/drug therapy* ; Penis/innervation* ; Peripheral Nerve Injuries/pathology* ; Phosphorylation ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects* ; rho-Associated Kinases/genetics*

Injury to peripheral nerves can lead to neuropathic pain, along with well-studied effects on sensory neurons, including hyperexcitability, abnormal spontaneous activity, and neuroinflammation in the sensory ganglia. Neuropathic pain can be enhanced by sympathetic activity. Peripheral nerve injury may also damage sympathetic axons or expose them to an inflammatory environment. In this study, we examined the lumbar sympathetic ganglion responses to two rat pain models: ligation of the L5 spinal nerve, and local inflammation of the L5 dorsal root ganglion (DRG), which does not involve axotomy. Both models resulted in neuroinflammatory changes in the sympathetic ganglia, as indicated by macrophage responses, satellite glia activation, and increased numbers of T cells, along with very modest increases in sympathetic neuron excitability (but not spontaneous activity) measured in ex vivo recordings. The spinal nerve ligation model generally caused larger responses than DRG inflammation. Plasticity of the sympathetic system should be recognized in studies of sympathetic effects on pain.
Action Potentials ; physiology ; Animals ; Disease Models, Animal ; Female ; Ganglia, Sympathetic ; pathology ; Glial Fibrillary Acidic Protein ; metabolism ; Hyperalgesia ; etiology ; Ligation ; adverse effects ; Macrophages ; pathology ; Male ; Neurogenic Inflammation ; etiology ; Pain ; etiology ; pathology ; Patch-Clamp Techniques ; Peripheral Nerve Injuries ; complications ; Rats ; Rats, Sprague-Dawley ; Receptors, Antigen, T-Cell, alpha-beta ; metabolism

The clinical effect of laparoscopic rectal cancer curative excision with pelvic autonomic nerve preservation (PANP) was investigated. This study evaluated the frequency of urinary and sexual dysfunction of 149 male patients with middle and low rectal cancer who underwent laparoscopic or open total mesorectal excision with pelvic autonomic nerve preservation (PANP) from March 2011 to March 2013. Eighty-four patients were subjected to laparoscopic surgery, and 65 to open surgery respectively. The patients were followed up for 12 months, interviewed, and administered a standardized questionnaire about postoperative functional outcomes and quality of life. In the laparoscopic group, 13 patients (18.37%) presented transitory postoperative urinary dysfunction, and were medically treated. So did 12 patients (21.82%) in open group. Sexual desire was maintained by 52.86%, un-ability to engage in intercourse by 47.15%, and un-ability to achieve orgasm and ejaculation by 34.29% of the patients in the laparoscopic group. Sexual desire was maintained by 56.36%, un-ability to engage in intercourse by 43.63%, and un-ability to achieve orgasm and ejaculation by 33.73% of the patients in the open group. No significant differences in urinary and sexual dysfunction between the laparoscopic and open rectal resection groups were observed (P>0.05). It was concluded that laparoscopic rectal cancer radical excision with PANP did not aggravate or improve sexual and urinary dysfunction.
Adult ; Autonomic Nervous System ; injuries ; Humans ; Laparoscopy ; adverse effects ; Male ; Middle Aged ; Peripheral Nerve Injuries ; etiology ; prevention & control ; Postoperative Complications ; Rectal Neoplasms ; surgery ; Sexual Dysfunction, Physiological ; etiology ; Urologic Diseases ; etiology

PURPOSE: This study was performed to examine the treatment of erectile dysfunction by use of superparamagnetic iron oxide nanoparticles-labeled human mesenchymal stem cells (SPION-MSCs) transplanted into the cavernous nerve injured cavernosa of rats as monitored by molecular magnetic resonance imaging (MRI). MATERIALS AND METHODS: Eight-week-old male Sprague-Dawley rats were divided into three groups of 10 rats each: group 1, sham operation; group 2, cavernous nerve injury; group 3, SPION-MSC treatment after cavernous nerve injury. Immediately after the cavernous nerve injury in group 3, SPION-MSCs were injected into the cavernous nerve injured cavernosa. Serial T2-weighted MRI was done immediately after injection and at 2 and 4 weeks. Erectile response was assessed by cavernous nerve stimulation at 2 and 4 weeks. RESULTS: Prussian blue staining of SPION-MSCs revealed abundant uptake of SPION in the cytoplasm. After injection of 1x10(6) SPION-MSCs into the cavernosa of rats, T2-weighted MRI showed a clear hypointense signal induced by the injection. The presence of SPION in the corpora cavernosa was confirmed with Prussian blue staining. At 2 and 4 weeks, rats with cavernous nerve injury had significantly lower erectile function than did rats without cavernous nerve injury (p<0.05). The group transplanted with SPION-MSCs showed higher erectile function than did the group without SPION-MSCs (p<0.05). The presence of SPION-MSCs for up to 4 weeks was confirmed by MRI imaging and Prussian blue staining in the corpus cavernosa. CONCLUSIONS: Transplanted SPION-MSCs existed for up to 4 weeks in the cavernous nerve injured cavernosa of rats. Erectile dysfunction recovered and could be monitored by MRI.
Animals ; Contrast Media/pharmacology ; Dextrans/*pharmacology ; Disease Models, Animal ; Drug Delivery Systems/methods ; *Erectile Dysfunction/diagnosis/etiology/therapy ; Magnetic Resonance Imaging/methods ; *Magnetite Nanoparticles ; Male ; Mesenchymal Stem Cell Transplantation/*methods ; Monitoring, Physiologic/methods ; Penis/*innervation ; *Peripheral Nerve Injuries/complications/diagnosis/physiopathology/therapy ; Rats ; Suspensions ; Treatment Outcome

OBJECTIVETo evaluate the erectile and ejaculatory function of sacral tumor patients after sacral nerve root resection and investigate the relationship of erectile and ejaculatory dysfunction (EED) with the level of sacral nerve injury.

METHODSThis retrospective study included 47 male patients aged 16 to 63 (32.6 +/- 6.8) years treated by sacral tumor resection between January 2008 and August 2013. According to the levels of the sacral nerve roots spared in surgery, the patients were divided into four groups: bilateral S1-S3 (n=16), unilateral S1-S3 (n=21), unilateral S1-S2 (n=6), and unilateral S1 (n=4). The patients were followed up for 12 to 41 (27.2 +/- 10.9) months by questionnaire investigation, clinic review, and telephone calls about their erectile and ejaculatory function at 3, 6 and 12 months after surgery and in August 2013.

RESULTSIn the bilateral S1-S3 group, the incidence rates of EED were 31.25% (5/16), 25% (4/16), and 12.5% (2/16) at 3, 6, and 12 months respectively after surgery, with recovery of erectile and ejaculatory function in August 2013. The incidence rates of EED in the unilateral S1-S3 group were 85.71% (18/21), 71.43% (15/21), 52.38% (11/21), and 42.86% (9/21) at 3, 6 and 12 months and in August 2013, respectively; those in the unilateral S1-S2 group were 100% (6/6), 83.33% (5/6), 83.33% (5/6), and 66.67% (4/6) at the four time points; and those in the unilateral S1 group were all 100% (4/4). No statistically significant differences were found in the incidence rate of EED among the patients of different ages or tumor types (P > 0.05).

CONCLUSIONThe incidence of postoperative EED in male patients treated by sacral tumor resection is closely related to the mode of operation. Sparing the S3 nerve root at least unilaterally in sacral tumor resection is essential for protecting the erectile and ejaculatory function of the patient.

Adolescent ; Adult ; Ejaculation ; physiology ; Erectile Dysfunction ; epidemiology ; etiology ; Female ; Humans ; Incidence ; Male ; Middle Aged ; Organ Sparing Treatments ; Peripheral Nervous System Neoplasms ; surgery ; Postoperative Complications ; epidemiology ; Postoperative Period ; Retrospective Studies ; Sacrum ; Spinal Nerve Roots ; injuries ; surgery ; Surveys and Questionnaires ; Young Adult

BACKGROUND: The minimally invasive plate osteosynthesis (MIPO) technique using periarticular locking plates may be a good option for the repair of displaced proximal humeral fractures. However, axillary nerve complications related to this technique may be underestimated. The purpose of this study is to evaluate the outcomes of the minimally invasive plating, focusing on the complications. METHODS: The records of 21 consecutive patients treated for proximal humerus fractures using the MIPO technique with locking plates were retrospectively reviewed. These patients were treated between March 2009 and March 2011 with a minimum one-year follow-up. The clinical function, complications, and radiological bony union were evaluated. RESULTS: All of the patients, with one exception, showed at least 90 degrees of flexion and abduction at the shoulder joint six months postoperatively. The average Constant scores at three months, six months, and one year follow-ups were 74.0 (range, 62 to 90), 79.4 (range, 64 to 91), and 82.7 (range, 66 to 92), respectively. All of the patients achieved bony union within the average of 3.2 months (range, 2 to 6 months). There was one case of delayed union, one case of intra-articular screw penetration, and one case of axillary nerve paresis (incomplete injury), which did not completely recover during the one year of follow-up. CONCLUSIONS: The MIPO technique using periarticular locking plates is a useful option for the treatment of selected cases of displaced proximal humeral fractures. However, nerve complications such as axillary nerve paresis should be considered along with implant-related complications when choosing patients for minimally invasive plating.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Bone Plates ; Female ; Fracture Fixation, Internal/*adverse effects ; Humans ; Male ; Middle Aged ; Minimally Invasive Surgical Procedures/adverse effects ; Peripheral Nerve Injuries/etiology ; Retrospective Studies ; Shoulder Fractures/*surgery ; Young Adult