Nature of DSP-4-Induced Neurotoxicity

Bortel, Aleksandra

doi:10.1007/978-3-030-71519-9_75-1

Cited by 1 publication

(1 citation statement)

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“…Because it crosses the blood-brain barrier, DSP4 can be administered intraperitoneally (IP) [38][39][40] and does not require surgical manipulations. After administration, DSP4 cyclizes to form an aziridinium derivative, which is an irreversible inhibitor of the norepinephrine transporter and inhibits norepinephrine reuptake with long lasting degenerative effects on LC-NA efferents [38][39][40]. Thus, DSP4 eliminates the LC-NA spinal projection, but spares projections of the A5 and A7 NA cell groups [41].…”

Section: Introductionmentioning

confidence: 99%

Locus Coeruleus Noradrenergic Modulation of Diurnal Corticosterone, Stress Reactivity, and Cardiovascular Homeostasis in Male Rats

et al. 2021

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Introduction: Activation of the locus coeruleus-noradrenergic (LC-NA) system during awakening is associated with an increase in plasma corticosterone and cardiovascular tone. These studies evaluate the role of the LC in this corticosterone and cardiovascular response. Methods: Male rats, on day 0, were treated IP with either DSP4 (50 mg/ kg body weight) (DSP), a LC-NA specific neurotoxin, or normal saline (SAL). On day 10, animals were surgically prepared with jugular vein [Hypothalamic–pituitary–adrenal (HPA) axis] or carotid artery (hemodynamics) catheters and experiments performed on day 14. HPA axis activity, diurnally (circadian) and after stress [transient hemorrhage (14 mL/kg body weight) or airpuff-startle], and basal and post-hemorrhage hemodynamics were evaluated. On day 16, brain regions from a subset of rats were dissected for norepinephrine and corticotropin-releasing factor (CRF) assay. Results: In DSP rats compared to SAL rats: 1) regional brain norepinephrine was decreased but there was no change in median eminence or olfactory bulb CRF content; 2) during HPA axis acrophase, the plasma corticosterone response was blunted; 3) after hemorrhage and airpuff-startle, the plasma adrenocorticotropic hormone response was attenuated, whereas the corticosterone response was dependent on stressor category; 4) under basal conditions, hemodynamic measures exhibited altered blood flow dynamics and systemic vasodilation; and 5) after hemorrhage, hemodynamics exhibited asynchronous responses. Conclusion: LC-NA modulation of diurnal and stress-induced HPA axis reactivity occurs via distinct neurocircuits. The integrity of the LC-NA system is important to maintain blood flow dynamics. The importance of increases in plasma corticosterone at acrophase to maintain short- and long-term cardiovascular homeostasis is discussed.

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