Novel Sodium Channel Inhibitor From Leeches

Abstract

Considering blood-sucking habits of leeches from surviving strategy of view, it can be hypothesized that leech saliva has analgesia or anesthesia functions for leeches to stay undetected by the host. However, no specific substance with analgesic function has been reported from leech saliva although clinical applications strongly indicated that leech therapy produces a strong and long lasting pain-reducing effect. Herein, a novel family of small peptides (HSTXs) including 11 members which show low similarity with known peptides was identified from salivary glands of the leech Haemadipsa sylvestris. A typical HSTX is composed of 22–25 amino acid residues including four half-cysteines, forming two intra-molecular disulfide bridges, and an amidated C-terminus. HSTX-I exerts significant analgesic function by specifically inhibiting voltage-gated sodium (NaV) channels (NaV1.8 and NaV1.9) which contribute to action potential electrogenesis in neurons and potential targets to develop analgesics. This study reveals that sodium channel inhibitors are analgesic substances in the leech. HSTXs are excellent candidates or templates for development of analgesics.

Prostaglandin E1 Is an Efficient Molecular Tool for Forest Leech Blood Sucking

“…The platelet aggregation-inhibiting activities of the collected fractions were tested and gathered every minute. Samples showing activity were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) ( 3 ).…”

“…This suggests that analgesic or anesthetic agents may be delivered to the host during the blood-sucking process. Furthermore, leeches must overcome hemostatic and vasoconstriction reactions in the host to ensure a steady and sustained blood flow to the feeding site ( 2 , 3 ).…”

“…Leeches can ingest a large amount of blood (>10-fold their own body weight) from their hosts within a short duration (20–30 min) ( 8 ), suggesting that they sustain host vasodilation and peripheral perfusion increase to take-up large volumes of blood while keeping the feeding time as short as possible ( 2 ). We previously revealed an analgesic peptide from Haemadipsa sylvestris ( 3 ). However, the specific analgesic, vasodilatory, and anti-inflammatory substances in leech saliva, and their corresponding pharmacological mechanisms, are yet to be identified.…”

Pharmacological activity and NMR solution structure of the leech peptide HSTX-I

“…Native HSTX-I was originally described as a modestly potent (IC 50 ~ 3 μM) blocker of rodent Na V 1.8 and Na V 1.9 currents by whole-cell patch-clamp electrophysiology in dissociated sensory neurons [16]. In our hands, when evaluated by whole-cell patch-clamp electrophysiology, synthetic HSTX-I (90 μM due to limited peptide solubility) had no effect on heterologously expressed hNa V 1.7 currents (101 ± 3%; Fig.…”

“…Recently, native HSTX-I, a small peptide toxin isolated from the leech Haemadipsa sylvestris, was shown to selectively modulate TTX-r channels, specifically Na V 1.8 and Na V 1.9, expressed in sensory neurons [16]. In the present study, we thus sought to explore the pharmacological activity and analgesic potential of synthetic HSTX-I.…”