Clinical and Immune Responses of Peripheral Chemical Sympathectomy in Enterovirus 71 Infection

The activation of the sympathetic nervous system, release of norepinephrine (NE), and adrenergic receptor signaling participate in and regulate the complicated enterovirus 71 (EV71) brainstem encephalitis (BE). The neurotoxin 6-hydroxydopamine (6-OHDA) selectively ablates sympathetic nerves and markedly depletes NE in innervated organs. Changes in the plasma levels of NE, severity score, cytokine profiles, and percentages of immunophenotype expression in 7-day-old Bltw : CD1 (ICR) mice infected with EV71, with or without 6-OHDA treatment, were compared. The survival rate (76.9%) of EV71-infected and 6-OHDA (30 μg/g)-treated mice was increased significantly. The clinical scores were decreased markedly on days 8-12 in MP4-infected and 6-OHDA-treated mice compared to those without treatment. The results showed that the plasma levels of NE, epinephrine, and dopamine were decreased on days 4–8 after 6-OHDA treatment and at most on day 8. The plasma levels of interleukin (IL)-12p70, tumor necrosis factor, IL-6, and IL-10 did not change significantly after 6-OHDA treatment. Interferon-γ levels decreased evidently on days 4, 6, and 8 after 6-OHDA treatment. The absolute events of CD3+CD4+, CD3+CD8+, and CD3+NK1.1+ cells of peripheral blood mononuclear cells were increased significantly in MP4-infected and 6-OHDA-treated mice compared to those without treatment. In splenocytes, the absolute cells of CD3−NK1.1+, CD3+NK1.1+ and CD11b+Gr-1+ cells of EV71-infected mice were increased significantly after 6-OHDA treatment. These findings suggested that 6-OHDA may be used a probe to explore clinical improvements and immune responses in the complicated EV71 infection. Taken together, peripheral chemical sympathectomy contribute to further understand the immunopathogenesis of EV71 BE with autonomic nervous system dysregulation.

Is axillary botulinum toxin efficient in controlling secondary Raynaud’s phenomenon? A case report

Raynaud’s phenomenon when secondary to underlying systemic disease such as systemic sclerosis occurs early in the disease course and progression can bring significant morbidity such as pain, digital ulceration, and necrosis. Standard medical therapies are aimed at promoting distal arterial vasodilation but are often inadequate in managing Raynaud’s phenomenon. Options for refractory cases include surgical and chemical sympathectomy with Botulinum neurotoxin type A (BoNT/A) hand injections but the latter can be associated with transient hand weakness. We describe the case of a 35-year-old woman with undifferentiated connective tissue disease, Raynaud’s phenomenon, and concomitant primary focal axillary hyperhidrosis for which she received axillary BoNT/A therapy every 6 months who noted significant improvement in her Raynaud’s phenomenon and hand arthralgias for 5 months following the axillary injections. This effect remained durable after 24 months of therapy. This improvement in Raynaud’s phenomenon after axillary BoNT/A has not been previously described.

Effect of the autonomic nervous system on cancer progression depends on the type of tumor: solid are more affected then ascitic tumors

Objectives. A number of recently published studies have shown that the sympathetic nervous system may influence cancer progression. There are, however, some ambiguities about the role of the parasympathetic nerves in the modulation of growth of different tumor types. Moreover, tumor models used for investigation of the autonomic neurotransmission role in the processes related to the cancer growth and progression are mainly of the solid nature. The knowledge about the nervous system involvement in the modulation of the development and progression of malignant ascites is only fragmental. Therefore, the aim of the present article was to summarize the results of our experimental studies focused on the elucidation of the role of the autonomic nervous system in the modulation of tumor growth in animals. We are summarizing data from studies, in which not only different experimental approaches in order to influence the autonomic neurotransmission, but also different tumor models have been used.Methods. Three different types of tumor models, namely solid rat intra-abdominal fibrosarcoma, solid murine subcutaneous melanoma, and rat ascites hepatoma, and three types of interventions have been used in order to modulate the autonomic neurotransmission, specifically chemical sympathectomy, subdiaphragmatic vagotomy, or the electric stimulation of the vagus nerve.Results. We have proved a strong stimulatory effect of the sympathetic nerves on the development and growth in both solid tumors, rat fibrosarcoma as well as murine melanoma, and significant inhibitory impact on the survival time of tumor-bearing animals. The progression of ascites hepatoma in rats was not influenced by chemical sympathectomy. Modulation of parasympathetic signalization by vagotomy or vagal nerve stimulation does not affect fibrosarcoma and ascites hepatoma growth and survival of the tumor-bearing rats.Conclusions. Based on the obtained data, it seems that the solid types of tumors are suitable substrate for the direct action of neurotransmitters released especially from the sympathetic nerves. In contrast, it appears that the malignant ascites are not under the direct autonomic nerves control; however, an indirect action via the immune functions modulation cannot be excluded.

Sympathectomized tumor-bearing mice survive longer but develop bigger melanomas

Objectives. Previously we have shown that 20 days after the tumor cells injection smaller melanomas have been developed in chemically sympathectomized mice in comparison with animals having intact sympathetic nervous system. However, it is known that chemical sympathectomy reduces the sympathetic neurotransmission only temporarily. In the present study, we monitored the survival of the sympathectomized mice with melanoma with an attempt to find out how long the suppressing effect of sympathectomy on the melanoma growth may endure.Methods. The chemical sympathectomy was performed by intraperitoneal injection of neurotoxin 6-hydroxydopamine in male C57BL/6J mice. Seven days later, the animals were injected subcutaneously with B16-F10 melanoma cells. Then, melanoma development, survival of the tumor-bearing mice and weight of the developed tumor mass were analyzed.Results. Sympathectomy delayed the development of the palpable tumors (18th day vs.14th day) and significantly prolonged the survival of the tumor-bearing mice (median 34 days vs. 29 days). However, the weight of the developed melanoma was significantly increased in the sympathectomized mice in comparison with the animals having intact sympathetic nervous system.Conclusions. The data of the present study showed that effect of the chemical sympathectomy, performed before the tumor growth induction, persisted even at the time when sympathetic nerves started to regenerate that resulted in a prolonged survival of the mice with melanoma. However, comparing to our previous study, in which we have shown a reduced tumor mass in earlier stages of the tumor growth, specifically 20 days after melanoma cells injection, now we indicate that in later stages of the melanoma progression, the tumor mass was significantly increased in sympathectomized animals. These contra-intuitive findings may indicate that interventions affecting the sympathetic nervous system may exert complex effect on the tumor progression. Based on these data we may suggest that the potential therapeutic interventions affecting the sympathetic signaling in the tumor tissue and its microenvironment should attenuate the sympathetic neurotransmission not only temporarily but till the complete regression of the tumor tissue.

Chemical Sympathectomy Restores Baroreceptor-Heart Rate Reflex and Heart Rate Variability in Rats With Chronic Nitric Oxide Deficiency

Nitric oxide (NO) plays a crucial role not only in regulation of blood pressure but also in maintenance of cardiac autonomic tone and its deficiency induced hypertension is accompanied by cardiac autonomic dysfunction. However, underlying mechanisms are not clearly defined. We hypothesized that sympathetic activation mediates hemodynamic and cardiac autonomic changes consequent to deficient NO synthesis. We used chemical sympathectomy by 6-hydroxydopamine to examine the influence of sympathetic innervation on baroreflex sensitivity (BRS) and heart rate variability (HRV) of chronic NG-nitro-L-arginine methyl ester (L-NAME) treated adult Wistar rats. BRS was determined from heart rate responses to changes in systolic arterial pressure achieved by intravenous administration of phenylephrine and sodium nitroprusside. Time and frequency domain measures of HRV were calculated from 5-min electrocardiogram recordings. Chronic L-NAME administration (50 mg/kg per day for 7 days orally through gavage) in control rats produced significant elevation of blood pressure, tachycardia, attenuation of BRS for bradycardia and tachycardia reflex and fall in time as well as frequency domain parameters of HRV. Sympathectomy completely abolished the pressor as well as tachycardic effect of chronic L-NAME. In addition, BRS and HRV improved after removal of sympathetic influence in chronic L-NAME treated rats. These results support the concept that an exaggerated sympathetic activity is the principal mechanism of chronic L NAME hypertension and associated autonomic dysfunction.