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Immunohistochemistry as a Strategy for Investigating the Functional Neuroanatomy of Drug Actions in the Brain
Published in Edythe D. London, Imaging Drug Action in the Brain, 2017
Immunohistochemistry has also been used to evaluate the neurotoxic effects of DSP-4, a drug which appears to be neurotoxic to noradrenergic axons (Fritschy and Grzanna, 1989). An interesting observation of this study was that the drug appeared to differentiate between different populations of noradrenergic axons arising from different nuclei, an effect similar to that caused by MDA, MDMA, and fenfluramine (vide supra). This effect, revealed by immunohistochemistry, inspired further pharmacological investigations into the mechanism of action of DSP-4, suggesting that this regional effect of the drug may be related to heterogeneity of noradrenergic uptake sites on different populations of noradrenergic neurons (Zaczek et al., 1990). Such studies further support the utility of immunohistochemistry in revealing the functional neuroanatomy of drug actions in brain.
Enzymes
Published in Stephen W. Carmichael, Susan L. Stoddard, The Adrenal Medulla 1986 - 1988, 2017
Stephen W. Carmichael, Susan L. Stoddard
Féty, Misére, Lambás-Señas et al. (1986) examined the effect of the neurotoxin DSP-4 on the catecholamine-synthesizing enzymes in the adrenal medulla and brain. They found slight increases in the activities of TH and DβH with relatively small changes in the activity of PNMT. They suggested that these changes were due to a reflex activation after denervation of sympathetic terminals by the neurotoxin.
Corticosterone and progesterone differentially regulate HPA axis and neuroimmune responses to stress in male rats
Published in Stress, 2020
Cara M. Hueston, Terrence Deak
A multitude of studies suggest increased expression of the pro-inflammatory cytokine interleukin-1β (IL-1) following stressor exposure is at least in part due to norepinephrine (NE) signaling, as alterations in NE tone have been found to affect central expression of IL-1 (Blandino Jr, Barnum, & Deak, 2006; Johnson et al., 2005, 2008; Ryan et al., 2016), as well as induce sickness-like behaviors (Morilak et al., 2005; Ryan et al., 2016). NE also increased peripheral cytokine expression in the spleen and plasma (Madden, Sanders, & Felten, 1995; Nance & Sanders, 2007). The actions of NE through its α1- and β-receptors is mechanistically dissociable, as administration of α1-antagonists reduced plasma IL-1, whereas antagonism of β-adrenergic receptors decreased hypothalamic IL-1 expression in rats following stressor exposure (Johnson et al., 2005). Lesions of the ventral noradrenergic bundle attenuated stress-induced IL-1 expression (Blandino Jr, Hueston, Barnum, Bishop, & Deak, 2013), whereas peripheral injection of the neurotoxin DSP-4 (which primarily lesions locus coeruleus NE neurons) blocked the increase in IL-1 expression induced by tailshock (Johnson et al., 2005). However, activation of the β2-adrenoceptors also increased levels of the IL-1 receptor type 2 (IL-1R2) in the hypothalamus (Ryan et al., 2016), which serves as a soluble decoy receptor with no known associated signaling pathways (Colotta, Dower, Sims, & Mantovani, 1994; Sims et al., 1993). Importantly, our recent work demonstrated that increased IL-1R2 emerged in a delayed fashion relative to IL-1 expression, suggesting it may aid in sequestering IL-1 signaling after stress cessation (Hueston & Deak, 2014a). Thus, acute stress challenges appear to induce not just increased IL-1 expression, but also to activate potential compensatory changes in gene expression (such as increased IL-1R2) that serve to temper stress-induced inflammatory signaling.
Does sympathetic nervous system modulate tumor progression? A narrative review of the literature
Published in Journal of Drug Assessment, 2020
Ioannis Stavropoulos, Angelos Sarantopoulos, Anastasios Liverezas
By 1985 a quite distinct perspective about the sympathetic innervation and its effect on tumors appeared. Grzanna et al. performed chemical sympathectomy in mice by two different chemical agents [6-hydroxydopamine (6-OHDA), N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4)] and a nerve growth factor antibody (anti-NGF) that causes immunosympathectomy [13]. All these three agents act with different mechanisms, namely: 6-OHDA acts like a selective neurotoxin for the sympathetic axons, DSP-4 reduces norepinephrine from central and peripheral noradrenergic neurons and treatment of newborn mice with anti-NGF causes immunosympathectomy. LPC-1 murine plasmacytoma cells were injected subcutaneously into the hindleg or intraperitoneally. Sympathectomy resulted in inhibition of the growth of LPC-1 tumors and was similar regardless of the agent used. The common point is that in all three cases the inhibition seems to be related with the destruction of sympathetic axons and not of cells of the adrenal medulla, which should alternate the concentration of circulated norepinephrine. Similarly, researchers did not detect neurochemical markers of sympathetic axons in LPC-1 tumors and thus the inhibition of tumor growth could not be explained by the lack of sympathetic innervation within tumors [13]. The same year Chelmicka-Schorr et al. studied the effect of 6-OHDA-induced sympathectomy on the growth of C-1300 neuroblastoma clonal lines [14]. Chelmicka-Schorr was the first who reported an inhibitory effect of 6-OHDA on tumor growth in 1976 [15], but she mentioned that it does not apply to all kinds of tumors. In 1978, she described that sympathectomy with 6-OHDA suppresses the growth of C-1300 neuroblastoma, and pretreatment of newborn mice with nerve growth factor can augment neuroblastoma growth [16]. However, the following study showed that sympathectomy had a different effect on different clonal lines. S-20 tumors were significantly suppressed in sympathectomized mice while NIE-115 tumors were not influenced and C-46 showed augmented progression in comparison to controls [14]. An explanation of this phenomenon may be the SNS action on tumor growth by secreting a trophic factor influencing C-1300 and its cholinergic clonal line, but no other lines that do not produce neurotransmitters [14]. Similarly, Tatsuta et al. described the inhibition of azoxymethane-induced colon carcinogenesis in Wistar rats that were sympathectomized by repeated injections of 6-OHDA [17]. The incidence of colon tumors was significantly lower in sympathectomized rats than in the control group, indicating that SNS may play a key role in colon carcinogenesis.