Endovascular occlusion of segmental arteries feeding the anterior spinal artery to stage endovascular thoracoabdominal aortic repair.

Objective: Minimally invasive segmental artery coil embolization was introduced to prevent spinal cord ischemia after endovascular repair of thoracoabdominal aortic aneurysms. There is no consensus on whether the endovascular occlusion of segmental arteries feeding directly the anterior radiculomedullary artery and anterior spinal artery can be safely performed without causing spinal cord ischemia. Our aim was to investigate the feasibility and clinical impact of endovascular occlusion of segmental arteries supplying the anterior spinal artery during minimally invasive segmental artery coil embolization in patients with thoracoabdominal aortic aneurysms. Methods: Between January 2018 and July 2020, 54 patients (36 male; mean age, 71.1 ± 9.3 years) underwent direct embolization of segmental arteries feeding the anterior radiculomedullary artery before endovascular repair of thoracoabdominal aortic aneurysms. End points included technical success of minimally invasive segmental artery coil embolization of segmental arteries, anterior radiculomedullary artery, neurological complications, and in-hospital mortality after minimally invasive segmental artery coil embolization and endovascular repair of thoracoabdominal aortic aneurysms. Results: The thoracoabdominal aortic aneurysm classification was type I (n = 8), type II (n = 24), type III (n = 11), and type IV (n = 11). During minimally invasive segmental artery coil embolization, 388 segmental arteries were occluded, each patient having 7.2 ± 3.1 coiled segmental arteries occluding 64.5% (25-100%) of open segmental arteries within the treated aortic segment. Altogether, 66 anterior radiculomedullary arteries were seen originating between Th8 and L3 levels from 85 (21.9%) segmental arteries. In 10 patients (18.5%), 2 large anterior radiculomedullary arteries were identified, and 1 patient (1.9%) showed 3 anterior radiculomedullary arteries on the spinal arteriography. No spinal cord ischemia or procedure-related complications occurred after minimally invasive segmental artery coil embolization. After 47.9 ± 39.4 days, all patients received endovascular repair of their thoracoabdominal aortic aneurysms. There was no in-hospital mortality. One male patient developed incomplete temporary spinal cord ischemia after endovascular repair. Conclusions: Minimally invasive segmental artery coil embolization of segmental arteries feeding the anterior spinal artery in patients with thoracoabdominal aortic aneurysms to prevent spinal cord ischemia after endovascular repair is feasible and clinically safe.

Modulation of chloride homeostasis by inflammatory mediators in dorsal root ganglion neurons.

BACKGROUND: Chloride currents in peripheral nociceptive neurons have been implicated in the generation of afferent nociceptive signals, as Cl- accumulation in sensory endings establishes the driving force for depolarizing, and even excitatory, Cl- currents. The intracellular Cl- concentration can, however, vary considerably between individual DRG neurons. This raises the question, whether the contribution of Cl- currents to signal generation differs between individual afferent neurons, and whether the specific Cl- levels in these neurons are subject to modulation. Based on the hypothesis that modulation of the peripheral Cl- homeostasis is involved in the generation of inflammatory hyperalgesia, we examined the effects of inflammatory mediators on intracellular Cl- concentrations and on the expression levels of Cl- transporters in rat DRG neurons. RESULTS: We developed an in vitro assay for testing how inflammatory mediators influence Cl- concentration and the expression of Cl- transporters. Intact DRGs were treated with 100 ng/ml NGF, 1.8 microM ATP, 0.9 microM bradykinin, and 1.4 microM PGE2 for 1-3 hours. Two-photon fluorescence lifetime imaging with the Cl--sensitive dye MQAE revealed an increase of the intracellular Cl- concentration within 2 hours of treatment. This effect coincided with enhanced phosphorylation of the Na+-K+-2Cl- cotransporter NKCC1, suggesting that an increased activity of that transporter caused the early rise of intracellular Cl- levels. Immunohistochemistry of NKCC1 and KCC2, the main neuronal Cl- importer and exporter, respectively, exposed an inverse regulation by the inflammatory mediators. While the NKCC1 immunosignal increased, that of KCC2 declined after 3 hours of treatment. In contrast, the mRNA levels of the two transporters did not change markedly during this time. These data demonstrate a fundamental transition in Cl- homeostasis toward a state of augmented Cl- accumulation, which is induced by a 1-3 hour treatment with inflammatory mediators. CONCLUSION: Our findings indicate that inflammatory mediators impact on Cl- homeostasis in DRG neurons. Inflammatory mediators raise intracellular Cl- levels and, hence, the driving force for depolarizing Cl- efflux. These findings corroborate current concepts for the role of Cl- regulation in the generation of inflammatory hyperalgesia and allodynia. As the intracellular Cl- concentration rises in DRG neurons, afferent signals can be boosted by excitatory Cl- currents in the presynaptic terminals. Moreover, excitatory Cl- currents in peripheral sensory endings may also contribute to the generation or modulation of afferent signals, especially in inflamed tissue.

Differential maturation of chloride homeostasis in primary afferent neurons of the somatosensory system.

Recent research into the generation of hyperalgesia has revealed that both the excitability of peripheral nociceptors and the transmission of their afferent signals in the spinal cord are subject to modulation by Cl(-) currents. The underlying Cl(-) homeostasis of nociceptive neurons, in particular its postnatal maturation, is, however, poorly understood. Here we measure the intracellular Cl(-) concentration, [Cl(-)]i, of somatosensory neurons in intact dorsal root ganglia of mice. Using two-photon fluorescence-lifetime imaging microscopy, we determined [Cl(-)]i in newborn and adult animals. We found that the somatosensory neurons undergo a transition of Cl(-) homeostasis during the first three postnatal weeks that leads to a decline of [Cl(-)]i in most neurons. Immunohistochemistry showed that a major fraction of neurons in the dorsal root ganglia express the cation-chloride co-transporters NKCC1 and KCC2, indicating that the molecular equipment for Cl(-) accumulation and extrusion is present. RT-PCR analysis showed that the transcription pattern of electroneutral Cl(-) co-transporters does not change during the maturation process. These findings demonstrate that dorsal root ganglion neurons undergo a developmental transition of chloride homeostasis during the first three postnatal weeks. This process parallels the developmental "chloride switch" in the central nervous system. However, while most CNS neurons achieve homogeneously low [Cl(-)]i levels - which is the basis of GABAergic and glycinergic inhibition - somatosensory neurons maintain a heterogeneous pattern of [Cl(-)]i values. This suggests that Cl(-) currents are excitatory in some somatosensory neurons, but inhibitory in others. Our results are consistent with the hypothesis that Cl(-) homeostasis in somatosensory neurons is regulated through posttranslational modification of cation-chloride co-transporters.

Caged capsaicins: New tools for the examination of TRPV1 channels in somatosensory neurons.

The vanilloid capsaicin, N-(4-hydroxy-3-methoxybenzyl)-8-methylnon-6-enamide, is the pungent ingredient of chili peppers and is used in pain research as an activating ligand of heat-sensitive transduction channels in nociceptive neurons. Here we describe the synthesis and application of two capsaicin derivatives modified at the hydroxy function of the vanillyl motif: alpha-carboxy-4,5-dimethoxy-2-nitrobenzyl-caged (CDMNB-caged) capsaicin and {7-[bis(carboxymethyl)amino]coumarin-4-yl}methoxycarbonyl-caged (BCMACMOC-caged) capsaicin. These compounds show dramatically reduced pungency, but release active capsaicin upon irradiation with UV light. CDMNB-caged capsaicin can be used to perform concentration-jump experiments, while BCMACMOC-caged capsaicin is membrane-impermeant and can be applied selectively to the intracellular or extracellular sides of a plasma membrane. Both compounds can serve as valuable research tools in pain physiology.