Two pathways for venom toxin entry consequent to injection of an Australian elapid snake venom.

Here we test and refute the hypothesis that venom toxins from an Australian elapid, the Eastern Brown snake (Pseudonaja textilis, PTx), solely require lymphatic transport to enter the circulation. Studies were made using anaesthetised non-recovery rats in which a marker dye (India ink) or highly potent PTx venom was injected into the hind paw. The studies required a means of inhibiting lymphatic function, as achieved by cooling of the test hind limb to low temperatures (~3 °C). Maintained entry of a non-lethal dose (0.15 mg/kg) and respiratory arrest consequent to injection of a lethal dose (1 mg/kg) of PTx venom at these low temperatures indicate that venom including toxin components enter the circulation directly via the vascular system, a process facilitated by, but not dependent on, lymphatic transport. Notably, the venom had a direct effect on vascular permeability markedly increasing this to allow extravasation of plasma albumin (MWt ~60 kDa).

Single mechanically-gated cation channel currents can trigger action potentials in neocortical and hippocampal pyramidal neurons.

The mammalian brain is a mechanosensitive organ that responds to different mechanical forces ranging from intrinsic forces implicated in brain morphogenesis to extrinsic forces that can cause concussion and traumatic brain injury. However, little is known of the mechanosensors that transduce these forces. In this study we use cell-attached patch recording to measure single mechanically-gated (MG) channel currents and their affects on spike activity in identified neurons in neonatal mouse brain slices. We demonstrate that both neocortical and hippocampal pyramidal neurons express stretch-activated MG cation channels that are activated by suctions of ~25mm Hg, have a single channel conductance for inward current of 50-70pS and show weak selectivity for alkali metal cations (i.e., Na(+)

Pharmacological approaches that slow lymphatic flow as a snakebite first aid.

BACKGROUND: This study examines the use of topical pharmacological agents as a snakebite first aid where slowing venom reaching the circulation prevents systemic toxicity. It is based on the fact that toxin molecules in most snake venoms are large molecules and generally first enter and traverse the lymphatic system before accessing the circulation. It follows on from a previous study where it was shown that topical application of a nitric oxide donor slowed lymph flow to a similar extent in humans and rats as well as increased the time to respiratory arrest for subcutaneous injection of an elapid venom (Pseudonaja textilis, Ptx; Eastern brown snake) into the hind feet of anaesthetized rats. METHODOLOGY/PRINCIPAL FINDINGS: The effects of topical application of the L-type Ca(2+) channel antagonist nifedipine and the local anesthetic lignocaine in inhibiting lymph flow and protecting against envenomation was examined in an anaesthetized rat model. The agents significantly increased dye-measured lymph transit times by 500% and 390% compared to controls and increased the time to respiratory arrest to foot injection of a lethal dose of Ptx venom by 60% and 40% respectively. The study also examined the effect of Ptx venom dose over the lethal range of 0.4 to 1.5 mg/kg finding a negative linear relationship between increase in venom dose and time to respiratory arrest. CONCLUSIONS/SIGNIFICANCE: The findings suggest that a range of agents that inhibit lymphatic flow could potentially be used as an adjunct treatment to pressure bandaging with immobilization (PBI) in snakebite first aid. This is important given that PBI (a snakebite first aid recommended by the Australian National Health and Medical research Council) is often incorrectly applied. The use of a local anesthetic would have the added advantage of reducing pain.

A pharmacological approach to first aid treatment for snakebite.

Snake venom toxins first transit the lymphatic system before entering the bloodstream. Ointment containing a nitric oxide donor, which impedes the intrinsic lymphatic pump, prolonged lymph transit time in rats and humans and also increased rat survival time after injection of venom. This pharmacological approach should give snakebite victims more time to obtain medical care and antivenom treatment.