scholarly journals The sGC activator BAY 60-2770 has potent erectile activity in the rat

2013 ◽  
Vol 304 (12) ◽  
pp. H1670-H1679 ◽  
Author(s):  
George F. Lasker ◽  
Edward A. Pankey ◽  
Terrence J. Frink ◽  
Jonathan R. Zeitzer ◽  
Korey A. Walter ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nerve Injury ◽  
Soluble Guanylate Cyclase ◽  
Crush Injury ◽  
Nerve Crush ◽  
Baseline Conditions ◽  
Sgc Activators ◽  
Sgc Stimulators ◽  
Nerve Crush Injury ◽  
Cavernosal Nerve

Nitric oxide (NO) is the principal mediator of penile erection, and soluble guanylate cyclase (sGC) is the receptor for NO. In pathophysiological conditions when sGC is inactivated and not responsive to NO or sGC stimulators a new class of agents called sGC activators increase the activity of NO-insensitive sGC and produce erection. The aim of this study was to investigate erectile responses to BAY 60-2770, a sGC activator, under physiological and pathophysiological conditions. In the present study increases in intracavernosal pressure (ICP) in response to intracavernosal (ic) injections of BAY 60-2770 were investigated under baseline conditions, when sGC was inhibited by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), when nitric oxide synthase (NOS) was inhibited by N-nitro-l-arginine methyl ester (l-NAME), and after cavernosal nerve crush injury. Under baseline conditions ic injections of BAY 60-2770 increase ICP, ICP/mean arterial pressure (MAP), and area under the ICP curve (AUC) and produce small decreases in MAP at the highest doses studied. BAY 60-2770 was very potent in its ability to induce erection and responses to BAY 60-2770 were enhanced by ODQ which attenuates erectile responses to sodium nitroprusside (SNP), diethylamine NONOate (DEA/NO), and cavernosal nerve stimulation. Responses to BAY 60-2770 were not altered by l-NAME or cavernosal nerve crush injury. These data indicate that BAY 60-2770 has potent erectile activity that is enhanced by ODQ and show that responses to BAY 60-2770 are not attenuated by NOS inhibition or cavernosal nerve injury. These results suggest that BAY 60-2770 would be effective in the treatment of erectile dysfunction when NO bioavailability is reduced, after pelvic nerve injury, and when sGC is oxidized.

scholarly journals Reduced Renshaw Recurrent Inhibition after Neonatal Sciatic Nerve Crush in Rats

2014 ◽  
Vol 2014 ◽  
pp. 1-11
Author(s):  
Liang Shu ◽  
Jingjing Su ◽  
Lingyan Jing ◽  
Ying Huang ◽  
Yu Di ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Sciatic Nerve ◽  
Peripheral Nerve ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Recurrent Inhibition ◽  
Crush Injury ◽  
Sciatic Nerve Crush ◽  
Nerve Crush ◽  
Nerve Crush Injury

Renshaw recurrent inhibition (RI) plays an important gated role in spinal motion circuit. Peripheral nerve injury is a common disease in clinic. Our current research was designed to investigate the change of the recurrent inhibitory function in the spinal cord after the peripheral nerve crush injury in neonatal rat. Sciatic nerve crush was performed on 5-day-old rat puppies and the recurrent inhibition between lateral gastrocnemius-soleus (LG-S) and medial gastrocnemius (MG) motor pools was assessed by conditioning monosynaptic reflexes (MSR) elicited from the sectioned dorsal roots and recorded either from the LG-S and MG nerves by antidromic stimulation of the synergist muscle nerve. Our results demonstrated that the MSR recorded from both LG-S or MG nerves had larger amplitude and longer latency after neonatal sciatic nerve crush. The RI in both LG-S and MG motoneuron pools was significantly reduced to virtual loss (15–20% of the normal RI size) even after a long recovery period upto 30 weeks after nerve crush. Further, the degree of the RI reduction after tibial nerve crush was much less than that after sciatic nerve crush indicatig that the neuron-muscle disconnection time is vital to the recovery of the spinal neuronal circuit function during reinnervation. In addition, sciatic nerve crush injury did not cause any spinal motor neuron loss but severally damaged peripheral muscle structure and function. In conclusion, our results suggest that peripheral nerve injury during neonatal early development period would cause a more sever spinal cord inhibitory circuit damage, particularly to the Renshaw recurrent inhibition pathway, which might be the target of neuroregeneration therapy.

scholarly journals Inflammatory Profiling of Schwann Cells in Contact with Growing Axons Distal to Nerve Injury

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Petr Dubový ◽  
Ilona Klusáková ◽  
Ivana Hradilová Svíženská
Keyword(s):  
Schwann Cells ◽  
Nerve Injury ◽  
Inflammatory Cytokines ◽  
Close Contact ◽  
Crush Injury ◽  
Sciatic Nerve Crush ◽  
Nerve Crush ◽  
Sciatic Nerves ◽  
Anti Inflammatory ◽  
Nerve Crush Injury

Activated Schwann cells distal to nerve injury upregulate inflammatory mediators, including cytokines. The goal of the present study was to investigate expression of proinflammatory (IL-1β, TNFα) and anti-inflammatory cytokines (IL-4, IL-10) in activated Schwann cells in relation to growing axons distal to crush injury of rat sciatic nerves. Seven days from sciatic nerve crush, transverse cryostat sections were cut 5 mm distal to lesion and incubated for double immunostaining to indicate Schwann cells (GFAP or S100b) and individual investigated cytokines or to demonstrate growing axons (GAP43). The Schwann cells of naïve sciatic nerves and those removed from sham-operated rats displayed similar weak immunoreactivity for the investigated cytokines. In contrast, increased intensity of cytokine immunofluorescence was found in Schwann cells distal to crush lesion. The cytokine-positive Schwann cells were found in close contact with growing axons detected by immunostaining for GAP43. The results of immunohistochemical analysis distal to nerve crush injury suggest that inflammatory profiling of Schwann cells including upregulation of both pro- and anti-inflammatory cytokines does not prevent growth of axons distal to nerve crush injury.

scholarly journals Citrus Naringenin Increases Neuron Survival in Optic Nerve Crush Injury Model by Inhibiting JNK-JUN Pathway

2021 ◽  
Vol 23 (1) ◽  
pp. 385
Author(s):  
Jie Chen ◽  
Hui Li ◽  
Changming Yang ◽  
Yinjia He ◽  
Tatsuo Arai ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Nerve Injury ◽  
Ganglion Cells ◽  
Crush Injury ◽  
Optic Nerve Crush ◽  
Nerve Crush ◽  
Injury Model ◽  
Nerve Crush Injury

Traumatic nerve injury activates cell stress pathways, resulting in neuronal death and loss of vital neural functions. To date, there are no available neuroprotectants for the treatment of traumatic neural injuries. Here, we studied three important flavanones of citrus components, in vitro and in vivo, to reveal their roles in inhibiting the JNK (c-Jun N-terminal kinase)-JUN pathway and their neuroprotective effects in the optic nerve crush injury model, a kind of traumatic nerve injury in the central nervous system. Results showed that both neural injury in vivo and cell stress in vitro activated the JNK-JUN pathway and increased JUN phosphorylation. We also demonstrated that naringenin treatment completely inhibited stress-induced JUN phosphorylation in cultured cells, whereas nobiletin and hesperidin only partially inhibited JUN phosphorylation. Neuroprotection studies in optic nerve crush injury mouse models revealed that naringenin treatment increased the survival of retinal ganglion cells after traumatic optic nerve injury, while the other two components had no neuroprotective effect. The neuroprotection effect of naringenin was due to the inhibition of JUN phosphorylation in crush-injured retinal ganglion cells. Therefore, the citrus component naringenin provides neuroprotection through the inhibition of the JNK-JUN pathway by inhibiting JUN phosphorylation, indicating the potential application of citrus chemical components in the clinical therapy of traumatic optic nerve injuries.

Abstract 3656: Estradiol Improves Neural Functional Recovery After Nerve Injury by Reducing Inhibition of the Hedgehog-signaling Pathway

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Haruki Sekiguchi ◽  
Masaaki Ii ◽  
Kentaro Jujo ◽  
Marie-Ange Renault ◽  
Tina Thorne ◽  
...  
Keyword(s):  
Treatment Group ◽  
Nerve Regeneration ◽  
Nerve Injury ◽  
Functional Recovery ◽  
Placebo Treatment ◽  
Crush Injury ◽  
Nerve Crush ◽  
Shh Signaling ◽  
Placebo Treatment Group ◽  
Nerve Crush Injury

Background: Prior data indicate that estradiol (E2) favorably affects neovascularization in injured tissue, and that Sonic Hedgehog (Shh)-induced neovascularization is critical for nerve regeneration; however, little is known about the relationship between E2 and Shh signaling. We tested the hypothesis that E2 potentiates nerve regeneration via Shh-activated neoangiogen-esis. Methods and Results: Ovariectomized mice were subjected to unilateral sciatic nerve crush injury and treated with either E2 (via locally administered biodegradable polymer) or placebo (polymer alone). E2 treatment resulted in greater functional recovery of the nerve as evaluated by both exercise duration (P<0.05) and motor nerve conduction velocity (P<0.05), and intraneural vascularity was significantly higher in E2-treated animals than in the placebo-treatment group (P<0.05). Analyses of mRNA expression in the injured nerves of placebo-treated mice showed that the Shh pathway was activated immediately after injury, but Shh expression declined substantially within 7 days. Shh activation persisted in the E2-treatment group; Shh expression on day 7 was greater in E2-treated animals than in the placebo-treatment group (P<0.05). The expression of Hedgehog-interacting protein (HIP), an endogenous Shh inactivator, was significantly downregulated 24 hours after E2 treatment, and HIP downregulation was attenuated by the E2-receptor blocker ICI, suggesting that E2 augments Shh signaling both my enhancing Shh expression and by inhibiting HIP. Inhibition of HIP expression by E2 was also observed in vitro in Schwann cells and endothelial cells. The expression of Ptc1 (Shh receptor) and Gli1 (a downstream target of Shh) was evaluated in Ptc1-LacZ and Gli1-LacZ mice after nerve-crush injury. X-gal staining demonstrated that E2 treatment upregulated both Ptc1 and Gli1 expression within 3 days of surgery. Conclusions: E2 accelerates the functional recovery of injured nerves by enhancing angiogenesis. We propose that these effects occur in part through the inhibition of the Shh inactivator HIP, thereby preserving Shh activity after nerve injury. These findings may have identified a novel regulatory mechanism for nerve repair via E2-enhaced, Shh-mediated angiogenesis.

scholarly journals Possible role of antioxidative capacity of (−)-epigallocatechin-3-gallate treatment in morphological and neurobehavioral recovery after sciatic nerve crush injury

2017 ◽  
Vol 27 (5) ◽  
pp. 593-613 ◽  
Author(s):  
Waleed M. Renno ◽  
Ludmil Benov ◽  
Khalid M. Khan
Keyword(s):  
Spinal Cord ◽  
Sciatic Nerve ◽  
Nerve Injury ◽  
Diameter Ratio ◽  
Crush Injury ◽  
Sciatic Nerve Crush ◽  
Axon Diameter ◽  
Nerve Crush ◽  
Myelin Thickness ◽  
Nerve Crush Injury

OBJECTIVEThis study examined the capacity of the major polyphenolic green tea extract (−)-epigallocatechin-3-gallate (EGCG) to suppress oxidative stress and stimulate the recovery and prompt the regeneration of sciatic nerve after crush injury.METHODSAdult male Wistar rats were randomly assigned to one of 4 groups: 1) Naïve, 2) Sham (sham injury, surgical control group), 3) Crush (sciatic nerve crush injury treated with saline), and 4) Crush+EGCG (sciatic nerve crush injury treated with intraperitoneally administered EGCG, 50 mg/kg). All animals were tested for motor and sensory neurobehavioral parameters throughout the study. Sciatic nerve and spinal cord tissues were harvested and processed for morphometric and stereological analysis. For the biochemical assays, the time points were Day 1, Day 7, Day 14, and Day 28 after nerve injury.RESULTSAfter sciatic nerve crush injury, the EGCG-treated animals (Crush+EGCG group) showed significantly better recovery of foot position and toe spread and 50% greater improvement in motor recovery than the saline-treated animals (Crush group). The Crush+EGCG group displayed an early hopping response at the beginning of the 3rd week postinjury. Animals in the Crush+EGCG group also showed a significant reduction in mechanical allodynia and hyperalgesia latencies and significant improvement in recovery from nociception deficits in both heat withdrawal and tail flick withdrawal latencies compared with the Crush group. In both the Crush+EGCG and Crush groups, quantitative evaluation revealed significant morphological evidence of neuroregeneration according to the following parameters: mean cross-sectional area of axons, myelin thickness in the sciatic nerve (from Week 4 to Week 8), increase of myelin basic protein concentration and gene expression in both the injured sciatic nerve and spinal cord, and fiber diameter to axon diameter ratio and myelin thickness to axon diameter ratio at Week 2 after sciatic nerve injury. However, the axon area remained much smaller in both the Crush+EGCG and Crush groups compared with the Sham and Naïve groups. The number of axons per unit area was significantly decreased in the Crush+EGCG and Crush groups compared with controls. Sciatic nerve injury produced generalized oxidative stress manifested as a significant increase of isoprostanes in the urine and decrease of the total antioxidant capacity (TAC) of the blood from Day 7 until Day 14. EGCG-treated rats showed significantly less increase of isoprostanes than saline-treated animals and also showed full recovery of TAC levels by Day 14 after nerve injury. In spinal cord tissue analysis, EGCG-treated animals showed induced glutathione reductase and suppressed induction of heme oxygenase 1 gene expression compared with nontreated animals.CONCLUSIONSEGCG treatment suppressed the crush-induced production of isoprostanes and stimulated the recovery of the TAC and was associated with remarkable alleviation of motor and sensory impairment and significant histomorphological evidence of neuronal regeneration following sciatic nerve crush injury in rats. The findings of this study suggest that EGCG can be used as an adjunctive therapeutic remedy for nerve injury. However, further investigations are needed to establish the antioxidative mechanism involved in the regenerative process after nerve injury. Only upregulation of glutathione reductase supports the idea that EGCG is acting indirectly via induction of enzymes or transcription factors.

Soluble guanylate cyclase in NO signaling transduction

2013 ◽  
Vol 33 (4) ◽  
pp. 193-205
Author(s):  
Jie Pan ◽  
Fangfang Zhong ◽  
Xiangshi Tan
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Signaling Transduction ◽  
Function Mechanism ◽  
The Past ◽  
No Signaling ◽  
Sgc Activators ◽  
Sgc Stimulators

AbstractNitric oxide (NO), a signaling molecule in the cardiovascular system, has been receiving increasing attention since Furchgott, Ignarro, and Murad were awarded the Nobel Prize in Physiology and Medicine for the discovery in 1998. Soluble guanylate cyclase (sGC), as an NO receptor, is a key metalloprotein in mediating NO signaling transduction. sGC is activated by NO to catalyze the conversion of guanosine 5′-triphosphate (GTP) to cyclic guanylate monophosphate (cGMP). The dysfunction of NO signaling results in many pathological disorders, including several cardiovascular diseases, such as arterial hypertension, pulmonary hypertension, heart failure and so on. Significant advances in its structure, function, mechanism, and physiological and pathological roles have been made throughout the past 15 years. We herein review the progress of sGC on structural, functional investigations, as well as the proposed activation/deactivation mechanism. The heme-dependent sGC stimulators and heme-independent sGC activators have also been summarized briefly.

scholarly journals Catfish Epidermal Preparation Accelerates Healing of Damaged Nerve in a Sciatic Nerve Crush Injury Rat Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Waleed M. Renno ◽  
Mohammad Afzal ◽  
Bincy Paul ◽  
Divya Nair ◽  
Jijin Kumar ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Nerve Injury ◽  
Axonal Regeneration ◽  
Crush Injury ◽  
Male Rats ◽  
Sciatic Nerve Crush ◽  
Spinal Neurons ◽  
Nerve Crush ◽  
Neurobehavioral Deficits ◽  
Nerve Crush Injury

Preliminary investigations showed that preparations from Arabian Gulf catfish (Arius bilineatus, Val) epidermal gel secretion (PCEGS) exhibit potent anti-inflammatory and healing properties as shown in our previous clinical trials for the healing of non-healing diabetic foot ulcers, chronic back pain, and some other neurological disorders. Here, we report for the first time a unique preparation containing only proteins and lipids (soluble protein fraction B, SPF-FB), derived from the PCEGS accelerated the healing and recovery of sensory-motor functions of experimental sciatic nerve crush injury in rats with its unique neuroprotective and neuroregenerative properties on the spinal neurons and peripheral nerve fibers. Male rats were randomly assigned to five groups: (I) NAÏVE, (II) SHAM, (III) CRUSH treated with saline, (IV) CRUSH + SPF-FB treated with 3 mg/kg intraperitoneally (IP) and (V) CRUSH + SPF-FB treated with 6 mg/kg subcutaneously (SC) groups. The crush groups III, IV and V underwent sciatic nerve crush injury, followed by treatment daily for 14 days with saline, SPF-FB IP and SPF-FB SC. All animals were tested for the neurobehavioral parameters throughout the 6 weeks of the study. Sciatic nerve and spinal cord tissues were processed for light and electron histological examinations, stereological analysis, immunohistochemical and biochemical examinations at Week 4 and Week 6 post-injury. Administration of SPF-FB IP or SC significantly enhanced the neurobehavioral sensory and motor performance and histomorphological neuroregeneration of the sciatic nerve-injured rats. The stereological evaluation of the axon area, average axon perimeters, and myelin thickness revealed significant histomorphological evidence of neuroregeneration in the FB-treated sciatic nerve crush injured groups compared to controls at 4 and 6 weeks. SPF-FB treatment significantly prevented the increased in NeuN-immunoreactive neurons, increased GFAP immunoreactive astrocytes, and decreased GAP-43. We conclude that SPF-FB treatment lessens neurobehavioral deficits, enhances axonal regeneration following nerve injury. We conclude that SPF-FB treatment lessens neurobehavioral deficits and enhances axonal regeneration following nerve injury, as well as protects spinal neurons and enhances subcellular recovery by increasing astrocytic activity and decreasing GAP-43 expression.

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