Caterpillar envenomation is a global health threat in the 21st century. Every direct or indirect contact with the urticating hairs of a caterpillar results in clinical manifestations ranging from local dermatitis symptoms to potentially life-threatening systemic effects. This is mainly due to the action of bioactive components in the venom that interfere with targets in the human body. The problem is that doctors are limited to relieve symptoms, since an effective treatment is still lacking. Only for Lonomia species an effective antivenom does exist. The health and economical damage are an underestimated problem and will be even more of a concern in the future. For some caterpillar species, the venom composition has been the subject of investigation, while for many others it remains unknown. Moreover, the targets involved in the pathophysiology are poorly understood. This review aims to give an overview of the knowledge we have today on the venom composition of different caterpillar species along with their pharmacological targets. Epidemiology, mode of action, clinical time course and treatments are also addressed. Finally, we briefly discuss the future perspectives that may open the doors for future research in the world of caterpillar toxins to find an adequate treatment.

Apamin is often cited as one of the few substances selectively acting on smallconductance Ca 2+ -activated potassium channels (K Ca 2). However, published pharmacological and structural data remain controversial. Here, we investigated the molecular pharmacology of apamin by two-electrode voltage-clamp in Xenopus laevis oocytes and patch-clamp in HEK293, COS7, and CHO cells expressing the studied ion channels, as well as in isolated rat brain neurons. The microtitre broth dilution method was used for antimicrobial activity screening. The spatial structure of apamin in aqueous solution was determined by NMR spectroscopy. We tested apamin against 42 ion channels (K Ca , K V , Na V , nAChR, ASIC, and others) and confirmed its unique selectivity to K Ca 2 channels. No antimicrobial activity was detected for apamin against Gram-positive or Gram-negative bacteria. The NMR solution structure of apamin was deposited in the Protein Data Bank. The results presented here demonstrate that apamin is a selective nanomolar or even subnanomolar-affinity K Ca 2 inhibitor with no significant effects on other molecular targets. The spatial structure as well as ample functional data provided here support the use of apamin as a K Ca 2-selective pharmacological tool and as a template for drug design.

Over the past decades, envenomation by caterpillars of Automeris spp. became an increasing health problem in Latin America. Accidental contact with the stinging spines of these caterpillars cause acute local pain, itching, inflammation and skin rashes that persists for days. Even when the cause is obvious, the exact molecular mechanisms responsible for the observed symptoms are yet to be elucidated. Here, we describe for the first time, an active compound in the venom and the study of the bioactivity of the venom extracted from the spines of the caterpillar Automeris zaruma. Electrophysiological screening of a library of membrane proteins important for pain and itch enabled us to investigate and reveal the mode of action of the venom of A. zaruma. Further mass spectrometric analysis (Q-TOF-MS) made it possible to establish a link between the bioactivity and the components found in the venom. We show that the spine extract of A. zaruma contains histamine that potently activates the four types of the human histamine receptors (H1R, H2R, H3R and H4R) with a selectivity preference towards H3R and H4R. Furthermore, a modulation of the target MRGPRX2 was found. Together, these findings are the first to explain the symptomology of A. zaruma envenomation, enabling us a better understanding of caterpillar envenomation and predict that the hurdle of the scarce efficacy of the currently used antihistaminic drugs can be overcome by including H3R and H4R blockers in the clinical used medication. Such an approach might be used for other caterpillar envenomation in the world and represent a significant improvement for the well-being of the patient.

To get more scientific information to support the medicinal uses of Ipomoea batatas, I. carnea, and I. pescaprae, phytochemical constituent analysis, toxicity and detoxification testing on normal and poisoned human cells, and ion channel inhibition using VGSCs, VGKCs and hERG channel were investigated. GC-MS and HPLC analysis were used for phytochemical screening and measuring the major compounds in 100 g leaf samples, which were 53.15-1446.93 mg oleamide in I. batatas -I. pes-caprae, 1.51-59.57 mg phytol in I. batatas -I. pes-caprae, and 39.04 mg α-amyrin and 8.09 mg β-amyrin in I. pes-caprae. The MTT assay showed no IC 50 value, and the comet assay revealed insignificant DNA damages (p > 0.05) on normal PBMCs. Detoxification efficacy for rice whisky-and herbicide-exposed cells was tested, and higher cell viability percentages were shown when the poisoned cells were treated with I. carnea and I. pes-caprae extracts compared with negative control. The hexane and acetonitrile extracts of I. batatas, I. carnea, and I. pes-caprae inhibited the VGSCs (Na v 1.6 and 1.8) and VGKCs (K v 1.1 and K v 10.1) channels, but not the hERG channel. The overall results indicated that the pharmacological activities of the studied plant extracts allowed them to be used as an excellent analgesic, an early marker in tumor formation useful for diagnosis and therapy of tumors, and treatments of poison and drug addiction, in addition to their antimicrobial, anti-inflammatory, and antipyretic activities. The plants can be used in daily human life with good cardiac safety and low risk for hERG inhibition.

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