Progressive Hemorrhagic Necrosis Research Articles

Timed sulfonylurea modulation improves locomotor and sensory dysfunction following spinal cord injury.

Traumatic spinal cord injury (SCI) results in immediate tissue necrosis and delayed secondary expansion of neurological damage, often resulting in lifelong paralysis, neurosensory dysfunction, and chronic pain. Progressive hemorrhagic necrosis (PHN) and excessive excitation are the main sources of secondary neural injury. Recent approaches to attenuate PHN by glibenclamide can improve locomotor function after SCI. However, use of glibenclamide can exacerbate development of SCI-induced chronic pain by inhibiting KATP channels to increase neuronal excitation and glial activation. In this study, we explored a treatment strategy involving administration of glibenclamide, which suppresses PHN, and diazoxide, which protects against neuronal excitation and inflammation, at different time intervals following spinal cord contusion. Our goal was to determine whether this combined approach enhances both sensory and motor function. Contusive SCI was induced at spinal segment T10 in adult rats. We found that KATP channels opener, diazoxide, decreased the hyperexcitability of primary sensory neurons after SCI by electrophysiology. Timed application of glibenclamide and diazoxide following contusion significantly improved locomotor function and mitigated development of SCI-induced chronic pain, as shown by behavioral evidence. Finally, we found that timed application of glibenclamide and diazoxide attenuates the inflammatory activity in the spinal cord and increases the survival of spinal matters following SCI. These preclinical studies introduce a promising potential treatment strategy to address SCI-induced dysfunction.

The Impact of Maternal Breast Milk in Preventing Necrotizing Enterocolitis: A Narrative Review

Context: Necrotizing enterocolitis (NEC), as a life-threatening gastrointestinal tract disease, is associated with high rates of morbidity and mortality. Extensive inflammation, progressive hemorrhagic necrosis, and overwhelming infection of the gut are reasons why NEC is known as a devastating disease in premature infants. Almost 45% of affected preterm infants die, and those who survive suffer from multiple complications. Human milk, the best food for newborns, plays a significant role in supporting the immune system. Both mother’s own milk (MOM) and donor human milk (DHM) are particularly important in the prevention and lessening of the severity of NEC. Evidence Acquisition: We searched PubMed, Elsevier, and Google Scholar databases for articles that investigated the correlation between NEC and human milk. Then all data were accessed about their relevancy to this current subject. Results: In summary, the purpose of this article is to firstly review the protective role of breast milk components against NEC, and secondly discussing the correlation between human milk and NEC in clinical studies. Human milk bio-components, including Lactoferrin, oligosaccharides, maternal soluble IgA, epidermal growth factor, transforming growth factor, prebiotic, probiotics, and antioxidants, have a protective effect against NEC. However, the importance of these components in donor human milk and the formula is underestimated. Conclusions: Human milk, as the first-choice of nutritional source, comprises a wide diversity of copious bio-components, which dwindle the risk and severity of NEC in many ways. The exact mechanisms are still unclear, the evidence strongly point out that human milk is superior to any other nutrition concerning protecting the gastrointestinal tract from NEC.

Potential of human dental stem cells in repairing the complete transection of rat spinal cord

Objective. The adult spinal cord of mammals contains a certain amount of neural precursor cells, but these endogenous cells have a limited capacity for replacement of lost cells after spinal cord injury. The exogenous stem cells transplantation has become a therapeutic strategy for spinal cord repairing because of their immunomodulatory and differentiation capacity. In addition, dental stem cells originating from the cranial neural crest might be candidate cell sources for neural engineering. Approach. Human dental follicle stem cells (DFSCs), stem cells from apical papilla (SCAPs) and dental pulp stem cells (DPSCs) were isolated and identified in vitro, then green GFP-labeled stem cells with pellets were transplanted into completely transected spinal cord. The functional recovery of rats and multiple neuro-regenerative mechanisms were explored. Main results. The dental stem cells, especially DFSCs, demonstrated the potential in repairing the completely transected spinal cord and promote functional recovery after injury. The major involved mechanisms were speculated below: First, dental stem cells inhibited the expression of interleukin-1β to reduce the inflammatory response; second, they inhibited the expression of ras homolog gene family member A (RhoA) to promote neurite regeneration; third, they inhibited the sulfonylurea receptor1 (SUR-1) expression to reduce progressive hemorrhagic necrosis; lastly, parts of the transplanted cells survived and differentiated into mature neurons and oligodendrocytes but not astrocyte, which is beneficial for promoting axons growth. Significance. Dental stem cells presented remarkable tissue regenerative capability after spinal cord injury through immunomodulatory, differentiation and protection capacity.

Absence of galectin-3 attenuates neuroinflammation improving functional recovery after spinal cord injury.

After spinal cord injury (SCI), a cascade of events begins. At first, there is physical damage with disruption of the blood-brain barrier (BBB) and the integrity of the nervous tissue. The disruption of central nervous system (CNS) BBB alters the endothelial permeability, the protein and chemokines expression and the propensity to release in situ inflammatory cytokines, overcoming anti-inflammatory signals, facilitating the attraction and entry of immune system cells into the injured spinal cord parenchyma (Gaudet et al., 2011). As a result, there is a neuroinflammatory response with changes in blood flow, edema, cell infiltration, apoptosis and release of axonal growth inhibitory factors. Nerve function loss occurs when the nerve impulse propagation is interrupted and do not reach its target. This disorder encompasses neuron and glia apoptosis, accompanied by Wallerian degeneration of disconnected axons, and CNS cells exposure to a hostile microenvironment that hampers axon regeneration (Mautes et al., 2000; Harkey et al., 2003). Additionally, the damage spreads further in a phenomenon called progressive hemorrhagic necrosis – PHN, with the appearance of petechial hemorrhagic foci and deterioration in areas outside the lesion epicenter during the next 2 – 24 hours after the trauma (Simard et al., 2007). Our laboratory investigates the role of galectin-3, a protein linked to mechanisms of inflammation, behind the cellular mechanisms of neural degeneration/regeneration with perspectives of a novel treatment (Mostacada et al., 2015).

Influence of glibenclamide on outcome in patients with type 2 diabetes and traumatic brain injury

Background and purposeThe influence of sulfonylurea receptor 1 (SUR1) and its inhibitor glibenclamide on progressive secondary hemorrhage (PSH), progressive hemorrhagic necrosis (PHN), and brain edema has been studied in rat models of traumatic brain injury (TBI) and ischemia. These studies indicate that blocking SUR1 may exert protective effects in terms of outcome. MethodsWe discuss the effects of glibenclamide on outcome in patients with type 2 diabetes mellitus and TBI. We collected demographic, clinical, and imaging data from the clinical records of TBI patients with type 2 diabetes who were admitted to the neurosurgery department at Shanghai 6th People's Hospital between 2001 and 2012. Data from patients who met the inclusion criteria were analyzed. Patients were divided into glibenclamide group and insulin group. ResultsOf 70 patients fit criteria for inclusion, no significant difference was observed except for age and fasting plasma glucose between the two groups. Outcome indicators, including GCS discharge, GOS discharge, length of study in hospital (LOS-H), and the presence of PSH showed no significant difference too (p>0.05), except for length of stay in neuro-intensive care unit (LOS-NICU) (p<0.05). Age, hours between the initial CT scan and the injury (HCT1) and GCS at admission were observed as factors associated with PSH after logistic regression. ConclusionsIn general, the use of glibenclamide to control plasma glucose after TBI had no significant effect on patient outcome at discharge but it could reduce the LOS-NICU (p<0.05). Glibenclamide also had no apparent effect on the presence of PSH in TBI patients with type 2 diabetes mellitus.

The Sur1-Trpm4 Channel in Spinal Cord Injury.

Spinal cord injury (SCI) is a major unsolved challenge in medicine. Impact trauma to the spinal cord shears blood vessels, causing an immediate 'primary hemorrhage'. During the hours following trauma, the region of hemorrhage enlarges progressively, with delayed or 'secondary hemorrhage' adding to the primary hemorrhage, and effectively doubling its volume. The process responsible for the secondary hemorrhage that results in early expansion of the hemorrhagic lesion is termed 'progressive hemorrhagic necrosis' (PHN). PHN is a dynamic process of auto destruction whose molecular underpinnings are only now beginning to be elucidated. PHN results from the delayed, progressive, catastrophic failure of the structural integrity of capillaries. The resulting 'capillary fragmentation' is a unique, pathognomonic feature of PHN. Recent work has implicated the Sur1-Trpm4 channel that is newly upregulated in penumbral microvessels as being required for the development of PHN. Targeting the Sur1-Trpm4 channel by gene deletion, gene suppression, or pharmacological inhibition of either of the two channel subunits, Sur1 or Trpm4, yields exactly the same effects histologically and functionally, and exactly the same unique, pathognomonic phenotype - the prevention of capillary fragmentation. The potential advantage of inhibiting Sur1-Trpm4 channels using glibenclamide is a highly promising strategy for ameliorating the devastating sequelae of spinal cord trauma in humans.

Comparative effects of glibenclamide and riluzole in a rat model of severe cervical spinal cord injury

Both glibenclamide and riluzole reduce necrosis and improve outcome in rat models of spinal cord injury (SCI). In SCI, gene suppression experiments show that newly upregulated sulfonylurea receptor 1 (Sur1)-regulated NCCa-ATP channels in microvascular endothelial cells are responsible for “persistent sodium currents” that cause capillary fragmentation and “progressive hemorrhagic necrosis”. Glibenclamide is a potent blocker of Sur1-regulated NCCa-ATP channels (IC50, 6–48nM). Riluzole is a pleotropic drug that blocks “persistent sodium currents” in neurons, but in SCI, its molecular mechanism of action is uncertain. We hypothesized that riluzole might block the putative pore-forming subunits of Sur1-regulated NCCa-ATP channels, Trpm4. In patch clamp experiments, riluzole blocked Sur1-regulated NCCa-ATP channels in endothelial cells and heterologously expressed Trpm4 (IC50, 31μM). Using a rat model of cervical SCI associated with high mortality, we compared the effects of glibenclamide and riluzole administered beginning at 3h and continuing for 7days after impact. During the acute phase, both drugs reduced capillary fragmentation and progressive hemorrhagic necrosis, and both prevented death. At 6weeks, modified (unilateral) Basso, Beattie, Bresnahan locomotor scores were similar, but measures of complex function (grip strength, rearing, accelerating rotarod) and tissue sparing were significantly better with glibenclamide than with riluzole. We conclude that both drugs act similarly, glibenclamide on the regulatory subunit, and riluzole on the putative pore-forming subunit of the Sur1-regulated NCCa-ATP channel. Differences in specificity, dose-limiting potency, or in spectrum of action may account for the apparent superiority of glibenclamide over riluzole in this model of severe SCI.

When replication teaches more than the original experiment — the saga of the unknown unknown

We recently published a description of the molecular mechanism involved in “progressive hemorrhagic necrosis”, a pathological process that evolves during several hours after spinal cord injury, that is attributable to progressive capillary fragmentation, and that is due to upregulation and activation of SUR1-regulated channels in microvascular endothelium. In this commentary, we reflect on the independent replication of our original experiment by Dr. Phillip Popovich and colleagues, and how their initial attempt at replication led to the unexpected finding that anisotropy of spinal cord tissues strongly influences the patterns of both primary and secondary hemorrhage that are observed after impact injury to the spinal cord.

Independent evaluation of the effects of glibenclamide on reducing progressive hemorrhagic necrosis after cervical spinal cord injury

These experiments were completed as part of an NIH-NINDS contract entitled “Facilities of Research Excellence – Spinal Cord Injury (FORE-SCI) – Replication”. Our goal was to replicate pre-clinical data from Simard et al. (2007) showing that glibenclamide, an FDA approved anti-diabetic drug that targets sulfonylurea receptor 1 (SUR1)-regulated Ca2+ activated, [ATP]i-sensitive nonspecific cation channels, attenuates secondary intraspinal hemorrhage and secondary neurodegeneration caused by hemicontusion injury in rat cervical spinal cord. In an initial replication attempt, the Infinite Horizons impactor was used to deliver a standard unilateral contusion injury near the spinal cord midline. Glibenclamide was administered continuously via osmotic pump beginning immediately post-SCI. The ability of glibenclamide to limit intraspinal hemorrhage was analyzed at 6, 12 and 24h post-injury using a colorimetric assay. Acute recovery (24h) of forelimb function was also assessed. Analysis of data from these initial studies revealed no difference between glibenclamide and vehicle-treated SCI rats. Later, it was determined that differences in primary trauma affect the efficacy of glibenclamide. Indeed, the magnitude and distribution of primary intraspinal hemorrhage was greater when the impact was directed to the dorsomedial region of the cervical hemicord (as in our initial replication experiment), as compared to the dorsolateral spinal cord (as in the Simard et al. experiment). In three subsequent experiments, injury was directed to the dorsolateral spinal cord. In each case, glibenclamide reduced post-traumatic hemorrhage 24–48h post-injury. In the third experiment, we also assessed function and found that acute reduction of hemorrhage led to improved functional recovery. Thus, independent replication of the Simard et al. data was achieved. These data illustrate that the injury model and type of trauma can determine the efficacy of pre-clinical pharmacological treatments after SCI.

Endothelial sulfonylurea receptor 1–regulated NCCa-ATP channels mediate progressive hemorrhagic necrosis following spinal cord injury

Acute spinal cord injury (SCI) causes progressive hemorrhagic necrosis (PHN), a poorly understood pathological process characterized by hemorrhage and necrosis that leads to devastating loss of spinal cord tissue, cystic cavitation of the cord, and debilitating neurological dysfunction. Using a rodent model of severe cervical SCI, we tested the hypothesis that sulfonylurea receptor 1-regulated (SUR1-regulated) Ca(2+)-activated, [ATP](i)-sensitive nonspecific cation (NC(Ca-ATP)) channels are involved in PHN. In control rats, SCI caused a progressively expansive lesion with fragmentation of capillaries, hemorrhage that doubled in volume over 12 hours, tissue necrosis, and severe neurological dysfunction. SUR1 expression was upregulated in capillaries and neurons surrounding necrotic lesions. Patch clamp of cultured endothelial cells exposed to hypoxia showed that upregulation of SUR1 was associated with expression of functional SUR1-regulated NC(Ca-ATP) channels. Following SCI, block of SUR1 by glibenclamide or repaglinide or suppression of Abcc8, which encodes for SUR1 by phosphorothioated antisense oligodeoxynucleotide essentially eliminated capillary fragmentation and progressive accumulation of blood, was associated with significant sparing of white matter tracts and a 3-fold reduction in lesion volume, and resulted in marked neurobehavioral functional improvement compared with controls. We conclude that SUR1-regulated NC(Ca-ATP) channels in capillary endothelium are critical to development of PHN and constitute a major target for therapy in SCI.

Recombinant Tissue Plasminogen Activator Treatment in Two Infants With Fulminant Meningococcemia

Fulminant meningococcemia defines a life-threatening disease with acute onset, severe septic shock, and progressive hemorrhagic necrosis of the skin. Despite advances in intensive care, the case fatality rate of this disease is still between 30% and 50%.1-5 Disseminated intravascular coagulation (DIC) with deposition of fibrin and histologically demonstrable widespread microvascular thromboses contributes significantly to the pathogenesis.6-9 Impairment of fibrinolysis caused by elevation of plasminogen activator inhibitor 1 (PAI-1), the physiologic inhibitor of tissue plasminogen activator, is part of these clotting abnormalities and has prognostic significance; the extent of elevation of PAI-1 is correlated to the development of shock, renal impairment, and mortality.10,11

Acquired Purpura Fulminans Induced by Alcohol and Acetaminophen

Purpura fulminans is a rare syndrome of progressive hemorrhagic necrosis of the skin that may present as a dermatologic emergency. It most commonly affects children during the convalescent phase of a streptococcal infection or a viral exanthem. In adults, it may be associated with sepsis or acquired causes. Its pathogenesis has challenged physicians for decades. It has been discovered that purpura fulminans is almost always associated with disseminated intravascular coagulation and can occur in subjects with inherited or acquired deficiencies of the protein C anticoagulant pathway. Patients with liver compromise may also be potential candidates for coagulopathies secondary to hepatic dysfunction and impaired protein synthesis. It is widely recognized that individuals who consume alcohol on a long-term basis may develop severe hepatotoxicity from ingestion of therapeutic doses of acetaminophen (500 to 1000 mg every 4 to 6 hours). We have observed a patient with chronic alcoholism in whom hepatotoxicity and purpura fulminans developed secondary to the ingestion of acetaminophen.

Microscopic analysis of early histopathological spinal cord alterations following trauma in normal and catecholamine-depleted cats

The progressive histopathological sequence over the first 3 hr after a 400 g-cm blunt injury to the spinal cord of catecholamine (CA)-intact and CA-depleted cats is described. Norepinephrine levels were measured in all animals. The experiments were designed to determine the role of CA in progressive hemorrhagic necrosis of the spinal cord by removing CA from one group of animals prior to trauma. A second group of CA-intact animals was subjected to identical experimentally-induced trauma. Upon analysis of the histopathological changes, it appears that the sequential nature of the development of hemorrhagic necrosis is both qualitatively and quantitatively similar in both experimental groups. The general conclusion is drawn that catecholamines in greater than normal amounts are present at the lesion site after trauma, but these catecholamines are probably not involved in the process of central hemorrhagic necrosis.