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Neuroendocrine Unit (A.C., E.S., A.G.), Multidisciplinary Institute on Cell Biology, 1900 La Plata, Argentina; School of Exact Sciences (A.C., A.G.), UNLP, 1900 La Plata, Argentina; and Division of Endocrinology and Metabolism (M.-J.V., R.C.G.), University Hospital, CH 1011 Lausanne, Switzerland
Address all correspondence and requests for reprints to: Eduardo Spinedi, Ph.D., Neuroendocrine Unit, IMBICE; cc 403, 1900 La Plata, Argentina. E-mail: imbice{at}satlink.com
Immune neuroendocrine interactions are vital for the individual’s
survival in certain physiopathological conditions, such as sepsis and
tissular injury. It is known that several animal venoms, such as those
from different snakes, are potent neurotoxic compounds and that their
main component is a specific phospholipase A type 2 (PLA2).
It has been described recently that the venom from Crotalus
durissus terrificus [snake venom (SV), in the present study]
possesses some cytotoxic effect in different in vitro
and in vivo animal models. In the present study, we
investigated whether SV and its main component, PLA2
(obtained from the same source), are able to stimulate both immune and
neuroendocrine functions in mice, thus characterizing this type of
neurotoxic shock. For this purpose, several in vivo and
in vitro designs were used to further determine the
sites of action of SV-PLA2 on the
hypothalamo-pituitary-adrenal (HPA) axis function and on the release of
the pathognomonic cytokine, tumor necrosis factor 
(TNF), of
different types of inflammatory stress. Our results indicate that SV
(25 µg/animal) and PLA2 (5 µg/animal), from the same
origin, stimulate the HPA and immune axes when administered (ip) to
adult mice; both preparations were able to enhance plasma glucose,
ACTH, corticosterone (B), and TNF plasma levels in a time-related
fashion. SV was found to activate CRH- and arginine vasopressin-ergic
functions in vivo and, in vitro, SV and
PLA2 induced a concentration-related (0.05–10 µg/ml)
effect on the release of both neuropeptides. SV also was effective in
changing anterior pituitary ACTH and adrenal B contents, also in a
time-dependent fashion. Direct effects of SV and PLA2 on
anterior pituitary ACTH secretion also were found to function in a
concentration-related fashion (0.001–1 µg/ml), and the direct
corticotropin-releasing activity of PLA2 was additive to
those of CRH and arginine vasopressin; the corticotropin-releasing
activity of both SV and PLA2 were partially reversed by the
specific PLA2 inhibitor, manoalide. On the other hand,
neither preparation was able to directly modify spontaneous and
ACTH-stimulated adrenal B output. The stimulatory effect of SV and
PLA2 on in vivo TNF release was confirmed
by in vitro experiments on peripheral mononuclear cells;
in fact, both PLA2 (0.001–1 µg/ml) and SV (0.1–10 µg/ml), as well
as concavalin A (1–100 µg/ml), were able to stimulate TNF output
in the incubation medium.
Our results clearly indicate that PLA2-dependent mechanisms are responsible for several symptoms of inflammatory stress induced during neurotoxemia. In fact, we found that this particular PLA2-related SV is able to stimulate both HPA axis and immune functions during the acute phase response of the inflammatory processes.
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