Minocycline targets multiple secondary injury mechanisms in traumatic spinal cord injury

Minocycline hydrochloride (MH), a semi-synthetic tetracycline derivative, is a clinically available antibi-otic and anti-inflammatory drug that also exhibits potent neuroprotective activities. It has been shown to target multiple secondary injury mechanisms in spinal cord injury, via its anti-inflammatory, anti-oxidant, and anti-apoptotic properties.The secondary injury mechanisms that MH can potentially target include inflammation, free radicals and oxidative stress, glutamate excitotoxicity, calcium influx, mitochondrial dysfunction, ischemia, hemorrhage, and edema. This review discusses the potential mechanisms of the multifaceted actions of MH. Its anti-inflammatory and neuroprotective effects are partially achieved through conserved mechanisms such as modulation of p38 mitogen-activated protein kinase (MAPK) and phos-phoinositide 3-kinase (PI3K)/Akt signaling pathways as well as inhibition of matrix metalloproteinases (MMPs). Additionally, MH can directly inhibit calcium influx through the N-methyl-D-aspartate (NMDA) receptors, mitochondrial calcium uptake, poly(ADP-ribose) polymerase-1 (PARP-1) enzymatic activity, and iron toxicity. It can also directly scavenge free radicals. Because it can target many secondary injury mechanisms, MH treatment holds great promise for reducing tissue damage and promoting functional re-covery following spinal cord injury.     

Alteration in extracellular amino acids after traumatic spinal cord injury

It has recently been demonstrated that N-methyl-D-aspartate antagonists limit tissue damage after spinal cord trauma, implicating excitatory amino acids in the secondary injury response. To determine whether spinal cord trauma alters the concentrations of extracellular amino acids, microdialysis was conducted in spinal cord during and after administration of impact trauma. Extracellular concentrations of excitatory, inhibitory, and nontransmitter amino acids were elevated after trauma, with the degree of increase related to severity of injury. Moderate trauma resulted in an immediate but transient increase (200-400%) in the extracellular levels of all amino acids measured. Severe trauma produced a more prolonged and significant increase (400-630%) in the concentrations of extracellular amino acids, including aspartate and glutamate. These results are consistent with the hypothesis that excitatory amino acids may contribute to delayed tissue injury after central nervous system trauma.     

Depression following traumatic spinal cord injury

OBJECTIVES: To describe the epidemiology of depression following traumatic spinal cord injury (SCI) and identify risk factors associated with depression. METHODS: This population-based cohort study followed individuals from date of SCI to 6 years after injury. Administrative data from a Canadian province with a universal publicly funded health care system and centralized databases were used. A Cox proportional hazards model was developed to identify risk factors. RESULTS: Of 201 patients with SCI, 58 (28.9%) were treated for depression. Individuals at highest risk were those with a pre-injury history of depression [hazard rate ratio (HRR) 1.6; 95% CI: 1.1-2.3], a history of substance abuse (HRR 1.6; 95% CI: 1.2-2.3) or permanent neurological deficit (HRR 1.6; 95% CI: 1.2-2.1). CONCLUSION: Depression occurs commonly and early in persons who sustain an SCI. Both patient and injury factors are associated with the development of depression. These should be used to target patients for mental health assessment and services during initial hospitalization and following discharge into the community.     

Spontaneous long-term remyelination after traumatic spinal cord injury in rats

The capability of the central nervous system to remyelinate axons after a lesion has been well documented, even though it had been described as an abortive and incomplete process. At present there are no long- term morphometric studies to assess the spinal cord (SC) remyelinative capability. With the purpose to understand this phenomenon better, the SC of seven lesionless rats and the SC of 21 rats subjected to a severe weight-drop contusion injury were evaluated at 1, 2, 4, 6, and 12 months after injury. The axonal diameter and the myelination index (MI=axolemmal perimeter divided by myelinated fiber perimeter) were registered in the outer rim of the cord at T9 SC level using a transmission electron microscope and a digitizing computer system. The average myelinated fiber loss was 95.1%. One month after the SC, 64% of the surviving fibers were demyelinated while 12 months later, only 30% of the fibers had no myelin sheath. The MI in the control group was 0.72±0.07 (X±S.D.). In the experimental groups, the greatest demyelination was observed two months after the lesion (MI=0.90±0.03), while the greatest myelination was observed 12 months after the injury (MI=0.83±0.02). There was a statistical difference (p<0.02) in MI between 2 and 12 months which means that remyelination had taken place. Remyelination was mainly achieved because of Schwann cells. The proportion of small fibers (diameter=0.5 μm or less) considered as axon collaterals, increased from 18.45% at 1 month to 27.66% a year after the contusion. Results suggest that remyelination is not an abortive phenomenon but in fact a slow process occurring parallel to other tissue plastic phenomena, such as the emission of axon collaterals.     

Critical role of connexin 43 in secondary expansion of traumatic spinal cord injury

Spinal cord injury (SCI) is often complicated by secondary injury as a result of the innate inflammatory response to tissue trauma and swelling. Previous studies have shown that excessive ATP release from peritraumatic regions contributes to the inflammatory response to SCI by activation of low-affinity P2X7 receptors. Because connexin hemichannels constitute an important route for astrocytic ATP release, we here evaluated the impact on post-traumatic ATP release of deletion of connexins (Cx30/Cx43) in astrocytes. In vivo bioluminescence imaging showed a significant reduction in ATP release after weight-drop injury in mice with deletion of Cx43 compared with Cx43-expressing littermates, both on a Cx30 knockout background. Moreover, astrogliosis and microglia activation were reduced in peritraumatic areas of those mice lacking Cx43; motor recovery was also significantly improved, and the traumatic lesion was smaller. Combined, these observations are consistent with a contribution by astrocytic hemichannels to post-traumatic ATP release that aggravates secondary injury and restrains functional recovery after experimental spinal cord injury. Connexins may thereby constitute a new therapeutic target in spinal cord injury.     

AIDA reduces glutamate release and attenuates mechanical allodynia after spinal cord injury

Spinal cord injury (SCI) leads to an increase in extracellular excitatory amino acid (EAA) concentrations, resulting in glutamate receptor-mediated excitotoxicity and central sensitization. To test contributions of group I metabotropic glutamate receptors (mGluRs) in SCI induced release of glutamate and in behavioral outcomes of central sensitization following injury, we administered 1-aminoindan-1,5-dicarboxylic acid (AIDA; 0.1 nmol intraspinally), a potent group I mGluR antagonist, to rats immediately after spinal cord contusion injury. EAAs were collected by microdialysis and quantified using HPLC. AIDA significantly decreased extracellular glutamate but not aspartate concentrations and significantly attenuated the development of mechanical but not thermal allodynia. These results suggest mGluRs play an important role in injury-induced EAA release and in central sensitization following SCI.     

Altered leukocyte gene expression after traumatic spinal cord injury:clinical implications

In addition to changes in motor and sensory function,individuals with spinal cord injury(SCI) experience immunological changes.These changes are clinically significant,as infections are the leading cause of death for this population.Along with increased infections,inflammation is commonly observed in persons with SCI,where it may promote many common medical consequences.These include elevated risk of cardiovascular disease,impaired wound healing,diabetes and neuropathic pain.It has also been proposed that chronic inflammation dampens neurological recovery.In order to identify therapeutic strategies to improve immune function,we need a greater understanding of the molecular changes that occur in immune cells after SCI.The purpose of this mini-review is to discuss two recent studies that used functional genomics to investigate gene expression in circulating leukocytes isolated from persons with SCI.In the future,the molecular pathways that are altered after SCI may be targeted to improve immunological function,as well as overall health and functional recovery,after SCI.     

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

正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     

Muscle after spinal cord injury

The morphological and contractile changes of muscles below the level of the lesion after spinal cord injury (SCI) are dramatic. In humans with SCI, a fiber‐type transformation away from type I begins 4–7 months post‐SCI and reaches a new steady state with predominantly fast glycolytic IIX fibers years after the injury. There is a progressive drop in the proportion of slow myosin heavy chain (MHC) isoform fibers and a rise in the proportion of fibers that coexpress both the fast and slow MHC isoforms. The oxidative enzymatic activity starts to decline after the first few months post‐SCI. Muscles from individuals with chronic SCI show less resistance to fatigue, and the speed‐related contractile properties change, becoming faster. These findings are also present in animals. Future studies should longitudinally examine changes in muscles from early SCI until steady state is reached in order to determine optimal training protocols for maintaining skeletal muscle after paralysis. Muscle Nerve, 2009     

Radiation-induced cellular changes in traumatic spinal cord injury

Summary Left dorsal cordotomy at the 11th thoracic vertebra was performed in mature female rats. Local exposures of 1,000 R of 280 kvp x rays were made within 10 min, 12, 24 36 or 48 hrs after injury. Tritiated thymidine (1 Ci/g body wt.) was injected i. v. 1 hr before death and necropsy examination 5, 18 or 30 days after surgery. Hematoxylin-stained sagittal sections (5 ) of the spinal cord were prepared for radioautographic examination. The parameters of magnitude and duration of changes in cell numbers and numbers of cells incorporating tritiated thymidine were determined for scar parenchymal cells (neuroglia and fibroblasts), macrophage, endothelia and mitotic cells.Irradiation modified the cellular composition of the developing scar tissue. These changes were due to a delay of proliferation in scar parenchymal and endothelial cell populations. A concomitant suppression of the number of cells incorporating tritiated thymidine occurred in 5-day old irradiated lesions. The magnitude and duration of these delays varied with the cell type and the time of irradiation after injury.These changes indicate that scar parenchymal and endothelial cells proliferatein situ from progenitor cell populations that were in the lesions at the time of irradiation.Macrophage cell numbers and numbers of these cells incorporating tritiated thymidine were not decreased after irradiation. It is, therefore, probable that the majority of the macrophage cells did not originate from a local progenitor cell population.

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Zusammenfassung Bei erwachsenen weiblichen Ratten wurde eine linksseitige dorsale Chordotomie in Höhe des 11. BWK durchgeführt. Lokale Röntgenbestrahlung mit einer Dosis von 1000 r bei 280 KVP binnen 10 min wurde 12, 24, 36 und 48 Std nach dem Trauma durchgeführt.³H-markiertes Thymidin (1 Ci/kg) wurde 1 Std vor der Tötung i.v. appliziet. Die autoptische Untersuchung erfolgte 5, 18 und 30 Tage nach dem Eingriff. Mit Hämatoxylin gefärbte Sagittalschnitte (5 Dicke) des Rückenmarks wurden autoradiographisch untersucht. Die Parameter der Größe und Dauer der Veränderungen der Zellzahl sowie dez Zahl der³H-Thymidin-markierten Zellen wurden für die Narbenparenchymzellen (Neuroglia und Fibroblasten), Makrophagen, Endothelzellen und Mitosen in der Narbe bestimmt.Die Bestrahlung veränderte die Zellzusammensetzung in dem sich entwickelnden Narbengewebe infolge verzögerter Proliferation der Parenchym- und Endothelzellen. In 5 Tage alten bestrahlten Läsionen erfolgte eine gleichzeitige Verminderung der³H-Thymidin inkorporierenden Zellen. Die Stärke und Dauer dieser Verzögerung schwankte je nach Zelltyp und Bestrahlungszeit nach dem Trauma.Die Befunde sprechen dafür, daß Narbenparenchyn- und Endothelzellen bei der Narbenbildung in situ aus ortsständigen Zellpopulationen gebildet werden, die bereits zum Zeitpunkt der Bestrahlung in der Läsion vorliegen.Die Zahl der Makrophagen sowie der³H-Thymidin-inkorporierenden Zellen war nach der Bestrahlung nicht vermindert. Es ist daher wahrscheinlich, daß die Mehrzahl der Makrophagen nicht aus ortsständigen Zellvorläufern entsteht.

     

Suicide following acute traumatic spinal cord injury.

The rate of suicide following spinal cord injury has not been extensively studied but appears to be greater than in the general population. Six patients who died by suicide, from a total of 342 patients who were treated for acute spinal cord injury over a 5 year period are described. Clinical features shared by this group of patients included being male; having schizoid, depressive or narcissistic personality traits; alcohol or drug abuse; family or significant others favouring death as a preferred option; and the development of significant depression.     

Necrostatin-1在小鼠脊髓损伤后继发性损伤中的作用

目的 探讨Necrostatin-1(Nec-1)在小鼠脊髓损伤后继发性损伤中的作用及机制。方法 将168只健康成年雌性LCR小鼠随机分为4组:对照组（48只）、脊髓损伤组（48只）、溶剂组（36只,鞘内注射4 μl二甲基亚砜）和治疗组[36只,鞘内注射4 μl Nec-1（4 mmol/L）]。采用血管夹钳夹小鼠脊髓建立脊髓损伤模型。伤后6、12、24、48 h采用免疫印迹法检测脊髓组织受体相互作用蛋白（RIP）1、3的表达;伤后24 h采用免疫共沉淀法评估RIP1和RIP3的相互作用;伤后24 h检测脊髓组织丙二醛（MDA）和活性氧簇（ROS）水平,电镜观察小鼠脊髓组织神经元线粒体损伤情况。结果 伤后48 h内,小鼠脊髓RIP1表达水平无明显变化;伤后6 h,小鼠脊髓RIP3表达水平明显增高,持续到伤后48 h。伤后24 h,治疗组和溶剂组RIP1和RIP3的表达水平均无明显差异;正常脊髓组织RIP1和RIP3相互作用较弱,脊髓损伤后RIP1和RIP3相互作用加强,而Nec-1显著抑制RIP1和RIP3相互作用。伤后24 h,脊髓神经元线粒体不同程度受损,而治疗组小鼠脊髓神经元线粒体结构保存相对较好。伤后24 h,脊髓组织MDA和ROS含量明显升高,而Nec-1能明显减少小鼠脊髓MDA和ROS含量。结论 小鼠脊髓损伤后,Nec-1通过抑制RIP1和RIP3的相互作用,进而抑制程序性坏死,减轻脊髓继发性损伤。Nec-1能降低ROS产物,减轻氧化应激损伤,保护线粒体功能。     

Tauroursodeoxycholic acid and secondary damage after spinal cord injury in rats.

Greater clinical understanding of the pivotal role of apoptosis in spinal cord injury (SCI) has led to new and innovative apoptosis-based therapies for patients with an SCI. Tauroursodeoxycholic acid (TUDCA) is a biliary acid with antiapoptotic properties. To our knowledge, this is the first study in the English language to evaluate the therapeutic efficacy of TUDCA in an experimental model of SCI. Thirty rats were randomized into three groups (sham-operated, trauma only, and trauma plus TUDCA treatment) of 10 each. In groups 2 and 3, spinal cord trauma was produced at the T8-T10 level via the Allen weight drop technique. Rats in group 3 were treated with TUDCA (200 mg/kg intraperitoneal) 1 min after trauma. The rats were killed either 24 h or 5 days after injury. The neuroprotective effect of TUDCA on injured spinal cord tissue and the effects of that agent on the recovery of hind-limb function were assessed. The efficacy of treatment was evaluated with histopathologic examination and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) analysis. Histopathologic characteristics were analyzed by comparison of hematoxylin-and-eosin stained specimens. Neurologic evaluations were performed 24 h, 3 days, and 5 days after trauma. Hind-limb function was assessed with the inclined plane technique of Rivlin and Tator and the modified version of Tarlov's grading scale. Twenty-four hours after injury, there was a significantly higher number of apoptotic cells in the lesioned spinal cord group than in the sham-operated control group. Treatment of the rats with TUDCA significantly reduced the number of apoptotic cells (4.52+/-0.30 vs. 2.31+/-0.24 in group 2) and the degree of tissue injury. Histopathologic examination showed that group 3 rats had better spinal cord architecture compared with group 2 rats. Five days after injury, the mean inclined plane angles in groups 1, 2, and 3 were 65.50 degrees +/- 2.09, 42.00 degrees +/- 2.74, and 53.50 degrees +/- 1.36. Motor grading of the rats revealed a similar trend. These differences were statistically significant (p<0.05). The mechanism of neuroprotection in the treated rats, although not yet elucidated, may be related to the marked antiapoptotic properties of TUDCA. A therapeutic strategy using TUDCA may eventually lead to effective treatment of SCI without toxic effects in humans.     

The fate and function of oligodendrocyte progenitor cells after traumatic spinal cord injury

Oligodendrocyte progenitor cells (OPCs) are the most proliferative and dispersed population of progenitor cells in the adult central nervous system, which allows these cells to rapidly respond to damage. Oligodendrocytes and myelin are lost after traumatic spinal cord injury (SCI), compromising efficient conduction and, potentially, the long-term health of axons. In response, OPCs proliferate and then differentiate into new oligodendrocytes and Schwann cells to remyelinate axons. This culminates in highly efficient remyelination following experimental SCI in which nearly all intact demyelinated axons are remyelinated in rodent models. However, myelin regeneration comprises only one role of OPCs following SCI. OPCs contribute to scar formation after SCI and restrict the regeneration of injured axons. Moreover, OPCs alter their gene expression following demyelination, express cytokines and perpetuate the immune response. Here, we review the functional contribution of myelin regeneration and other recently uncovered roles of OPCs and their progeny to repair following SCI.     

Function of microglia and macrophages in secondary damage after spinal cord injury

Spinal cord injury （SCI） is a devastating type of neurological trauma with limited therapeutic op- portunities. The pathophysiology of SCI involves primary and secondary mechanisms of injury. Among all the secondary injury mechanisms, the inflammatory response is the major contrib- utor and results in expansion of the lesion and further loss of neurologic function. Meanwhile, the inflammation directly and indirectly dominates the outcomes of SCI, including not only pain and motor dysfunction, but also preventingneuronal regeneration. Microglia and macrophages play very important roles in secondary injury. Microglia reside in spinal parenchyma and survey the microenvironment through the signals of injury or infection. Macrophages are derived from monocytes recruited to injured sites from the peripheral circulation. Activated resident microglia and monocyte-derived macrophages induce and magnify immune and inflammatory responses not only by means of their secretory moleculesand phagocytosis, but also through their influence on astrocytes, oligodendrocytes and demyelination. In this review, we focus on the roles of mi- croglia and macrophages in secondary injury and how they contribute to the sequelae of SCI.