Spinal Cord Injury (SCI) Switches How GABA Affects Nociceptive Plasticity

Research has shown that spinal cord injury (SCI) can induce neural hyperexcitability within the spinal cord that facilitates nociceptive reflexes. Nociceptive inputs have been shown to sensitize spinal nociceptive systems, inducing a learning deficit and enhanced mechanical reactivity (EMR) in spinally transected rats. Nociceptive sensitization has been linked to abnormal GABA-mediated inhibition of nociceptive neurons within the spinal cord. However, underlying changes remain poorly understood. This dissertation were designed to test the effect of blocking GABA transmission on nociceptive sensitization after spinal cord injury. Experiment 1 focused on the effect of bicuculline on shock-induced EMR in transected rats, finding blocking effect of bicuculline. Experiments 2 and 4 investigated whether bicuculline blocks inflammation-induced EMR. I found bicuculline pretreatment prevented both LPS and capsaicin-induced EMR. Further, capsaicin-induced EMR was reversed by bicuculline treatment (Experiment 5). Experiment 6 found that other GABA receptor antagonists also blocked the capsaicin-induced EMR. Of clinical importance, bicuculline blocked indices of capsaicin-induced central sensitization at the mRNA level (Experiment 7) and protein level (Experiment 8). These results suggest that bicuculline blocks central sensitization in spinally transected rats and that GABA has an excitatory effect. To explore whether a spinal transection alters GABA function, similar experimental manipulations were conducted in intact rats. Experiment 9 found that bicuculline treatment per se induced EMR and failed to block the capsaicin-induced EMR. Experiments 10 and 11 found that bicuculline did not block central sensitization at the cellular level. These results suggest that GABA inhibits nociceptive processing in intact rats, but promotes it after spinal injury. Experiment 12 explored that spinal transection induced a downregulation of the membrane-bound KCC2, and thereby changed intracellular chloride homeostasis. To test whether drug manipulation targeting chloride co-transporters switch the role of GABA in nociceptive sensitization, channel blockers targeting KCC2 and NKCC1 were tested. Experiment 13 showed that blocking KCC2 in intact rats causes bicuculline to attenuate capsaicin-induced EMR. Conversely, Experiment 14 showed that blocking NKCC1 in transected rats switches how bicuculline affects capsaicin-induced EMR. Taken together, my results suggest that spinal cord injury switches the effect of GABA in nociceptive sensitization by altering the intracellular chloride homeostasis

Motor neuron-derived Thsd7a is essential for zebrafish vascular development via the Notch-dll4 signaling pathway.

BackgroundDevelopment of neural and vascular systems displays astonishing similarities among vertebrates. This parallelism is under a precise control of complex guidance signals and neurovascular interactions. Previously, our group identified a highly conserved neural protein called thrombospondin type I domain containing 7A (THSD7A). Soluble THSD7A promoted and guided endothelial cell migration, tube formation and sprouting. In addition, we showed that thsd7a could be detected in the nervous system and was required for intersegmental vessels (ISV) patterning during zebrafish development. However, the exact origin of THSD7A and its effect on neurovascular interaction remains unclear.ResultsIn this study, we discovered that zebrafish thsd7a was expressed in the primary motor neurons. Knockdown of Thsd7a disrupted normal primary motor neuron formation and ISV sprouting in the Tg(kdr:EGFP/mnx1:TagRFP) double transgenic zebrafish. Interestingly, we found that Thsd7a morphants displayed distinct phenotypes that are very similar to the loss of Notch-delta like 4 (dll4) signaling. Transcript profiling further revealed that expression levels of notch1b and its downstream targets, vegfr2/3 and nrarpb, were down-regulated in the Thsd7a morphants. These data supported that zebrafish Thsd7a could regulate angiogenic sprouting via Notch-dll4 signaling during development.ConclusionsOur results suggested that motor neuron-derived Thsd7a plays a significant role in neurovascular interactions. Thsd7a could regulate ISV angiogenesis via Notch-dll4 signaling. Thus, Thsd7a is a potent angioneurin involved in the development of both neural and vascular systems

Spontaneous Dissecting Aneurysm of the Renal Artery: A Case Report

Primary dissecting aneurysms of the renal artery are exceedingly rare. The triad of flank pain, hematuria, and hypertension of acute onset in the absence of urinary obstruction should suggest this rare condition. We report a case of spontaneous dissecting aneurysm of the renal artery treated using conservative medical treatment. The diagnosis, therapeutic management, and outcome are discussed

Identification and subcellular localization of a novel Cu,Zn superoxide dismutase of Mycobacterium tuberculosis

AbstractPeriplasmic copper, zinc superoxide dismutases (Cu,ZnSOD) of several Gram-negative pathogens have been shown to play an important role in protection against exogenous superoxide radicals and in determining virulence of the pathogens. Here we report the cloning and characterization of the sodC gene, encoding Cu,ZnSOD, from the Gram-positive Mycobacterium tuberculosis. The predicted protein sequence contains 240 amino acids with a putative signal peptide at the N-terminus and shows ∼25% identity to other bacterial sodC. Recombinant proteins of a full-length sodC and a truncated form lacking the putative signal peptide were overexpressed in Escherichia coli and affinity purified. Renatured recombinant M. tuberculosis sodC protein possessed characteristics of a Cu,ZnSOD. Immunoblotting with an antiserum against the recombinant M. tuberculosis Cu,ZnSOD allowed detection of a single polypeptide in the lysate of M. tuberculosis. This polypeptide has a similar size as the recombinant protein without the putative signal peptide indicating that the endogenous Cu,ZnSOD in M. tuberculosis might be processed and secreted. Furthermore, immunogold electron microscopic image showed that Cu,ZnSOD is located in the periphery of M. tuberculosis. The enzymatic activity and subcellular localization of this novel Cu,ZnSOD suggest that it may play a role in determining virulence of M. tuberculosis

Learning about time within the spinal cord: evidence that spinal neurons can abstract and store an index of regularity

Prior studies have shown that intermittent noxious stimulation has divergent effects on spinal cord plasticity depending upon whether it occurs in a regular [fixed time (FT)] or irregular [variable time (VT)] manner: In spinally transected animals, VT stimulation to the tail or hind leg impaired spinal learning whereas an extended exposure to FT stimulation had a restorative/protective effect. These observations imply that lower level systems are sensitive to temporal relations. Using spinally transected rats, it is shown that the restorative effect of FT stimulation emerges after 540 shocks; fewer shocks generate a learning impairment. The transformative effect of FT stimulation is related to the number of shocks administered, not the duration of exposure. Administration of 360 FT shocks induces a learning deficit that lasts 24 hours. If a second bout of FT stimulation is given a day after the first, it restores the capacity to learn. This savings effect implies that the initial training episode had a lasting (memory-like) effect. Two bouts of shock had a transformative effect when applied at different locations or at difference frequencies, implying spinal systems abstract and store an index of regularity (rather than a specific interval). Implications of the results for step training and rehabilitation after injury are discussed

Toona sinensis

Toona sinensis leaf (TSL) is commonly used as a vegetable and in spice in Asia. In this study, feeding with aqueous extract of TSL (TSL-A) alleviated oxidative stress and recovered the motility and functions of sperm in rats under oxidative stress. Protein expressions in testes identified by proteomic analysis and verified by Western blot demonstrated that TSL-A not only downregulated the level of glutathione transferase mu6 (antioxidant system), heat shock protein 90 kDa-β (protein misfolding repairing system), cofilin 2 (spermatogenesis), and cyclophilin A (apoptosis) but also upregulated crease3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 (steroidogenesis), heat shock glycoprotein 96, and pancreatic trypsin 1 (sperm-oocyte interaction). These results indicate that TSL-A promotes the functions of sperm and testes via regulating multiple testicular proteins in rats under oxidative stress, suggesting that TSL-A is a valuable functional food supplement to improve functions of sperm and testes for males under oxidative stress

Dynamic Effects of Axial Loading on the Lumbar Spine During Magnetic Resonance Imaging in Patients with Suspected Spinal Stenosis

BackgroundPrevious studies have shown that axial compression in extension (ACE) of the spine during magnetic resonance imaging (MRI) has revealed unexpected pathological features compared with the conventional psoas-relaxed position (PRP) used in imaging. The purpose of this study was to evaluate the dynamic effect of axial loading on lumbar spinal stenosis using MRI in patients with spinal stenosis.MethodsA total of 14 women and 11 men with lumbar spinal stenosis were examined in both PRP and ACE positions. We calculated the dural-sac cross-sectional area (DCSA) to evaluate severity of spinal canal stenosis. DCSA, as well as the dural-sac anteroposterior diameter (DAPD) and dural-sac transverse diameter (DTD) in both positions were measured using a digital image view station. A paired t test determined the differences in DCSA, DAPD and DTD between the two positions at each intervertebral disc level.ResultsAxial loading increased severity of lumbar spinal stenosis during MRI, as demonstrated by a decrease in DCSA from 20.5% to 6.3% (mean, 11.40 ± 3.66%) between the PRP and ACE positions (p < 0.01). Significant differences were also noted in DAPD and DTD between the PRP and ACE positions (p < 0.01). A significant correlation was found between the decrease in mean DCSA and that in DAPD and DTD. The decrease in mean DCSA, DAPD and DTD following axial compression was greatest at the L4/5 and L5/S1 levels.ConclusionAxial loading increases severity of lumbar canal stenosis and the effect of axial loading on MRI examination is greatest at the L4/5 and L5/S1 levels