Peptides from Scorpion Venom and Autoimmune

diseases

K. George Chandy, Department of Physiology and Biophysics, University of

California Irvine

Lancet 2, 1021, 1983

The authors of the Lancet Letter suggest that the improvement is due to improved nerve conduction. But would such an improvement of nerve conduction result

in a 2 month remission of MS?

Is it possible that scorpion venom blocked Kv1.3 potassium channels in disease-associated myelin-specific effector-memory T cells in this patient,

suppressed the autoimmune response and thereby produced the remission of MS?

Kv1.3 channels in effector memory T cells are considered an attractive and safe target for autoimmune disease

therapy.

Wulff et al, J Clin Invest. 2003;111:1703-13; Chandy et al., Trends Pharmacol Sci. 2004;25:280-9; Rus et al., Proc Natl Acad Sci U S A. 2005;102:11094-9; Beeton et al., Proc Natl Acad Sci U S A. 2006;103:17414-9.

Scorpion toxins block the Kv1.3 channel

Toxin: IC50 ADWX-1 toxin: 1 pMHsTx1: 12 pMOSK1 toxin: 14 pMPi2: 50 pMHongotoxin: 86 pMMargatoxin: 110 pMAgitoxin-2: 200 pMPi3: 500 pMKaliotoxin: 650 pMAnuroctoxin: 760 pMNoxiustoxin: 1000 pMAam-KTX: 1100 pM Hemitoxin: 2000 pMCharybdotoxin: 3000 pMTityustoxin-Ka: 4000 pMCss20: 7200 pM Pi1: 11000 pMKbot1: 15000 pMLmKTx10: 28000 pMMaurotoxin: 150000 pMParabuthus Tx3: 492000 pMParabuthus Tx1: 800000 pM

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Kv1.3 blockers from scorpion venom are immunosuppressive

Price M. et al., Charybdotoxin inhibits proliferation and interleukin 2 production in human peripheral blood lymphocytes. Proc Natl Acad Sci U S A. 1989;86:10171-5.

Freedman BD et al., Evidence for voltage modulation of IL-2 production in mitogen-stimulated human peripheral blood lymphocytes. J Immunol. 1992;149:3784-94.

Lin CS, et al. Voltage-gated potassium channels regulate calcium-dependent pathways involved in human T lymphocyte activation. J Exp Med. 1993;177:637-45.

Koo GC et al., Blockade of the Voltage-gated potassium channel Kv1.3 inhibits immune responses in vivo. J Immunol. 1997;158:5120-8.

Beeton C, et al. Selective blocking of voltage-gated K+ channels improves experimental autoimmune encephalomyelitis and inhibits T cell activation. J Immunol. 2001;166:936-44.

Kv1.3 blockers from scorpion venom are effective in a rat model of multiple

sclerosisBeeton C, et al. Selective blocking of voltage-gated K+

channels improves experimental autoimmune encephalomyelitis and inhibits T cell activation.

J Immunol. 2001;166:936-44. Kaliotoxin (KTX), a blocker of voltage-gated potassium channels (Kv), is highly selective for Kv1.1 and Kv1.3. First, Kv1.3 is expressed by T lymphocytes. Blockers of Kv1.3 inhibit T lymphocyte activation. Second, Kv1.1 is found in paranodal regions of axons in the central nervous system. Kv blockers improve the impaired neuronal conduction of demyelinated axons in vitro and potentiate the synaptic transmission. Therefore, we investigated the therapeutic properties of KTX via its immunosuppressive and symptomatic neurological effects, using experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. The T line cells used to induce adoptive EAE were myelin basic protein (MBP)-specific, constitutively contained mRNA for Kv1.3. and expressed Kv1.3. These channels were shown to be blocked by KTX. Activation is a crucial step for MBP T cells to become encephalitogenic. The addition of KTX during Ag-T cell activation led to a great reduction in the MBP T cell proliferative response, in the production of IL-2 and TNF, and in Ca(2+) influx. Furthermore, the addition of KTX during T cell activation in vitro led a decreased encephalitogenicity of MBP T cells. Moreover, KTX injected into Lewis rats impaired T cell function such as the delayed-type hypersensitivity. Lastly, the administration of this blocker of neuronal and lymphocyte channels to Lewis rats improved the symptoms of EAE. We conclude that KTX is a potent immunosuppressive agent with beneficial effects on the neurological symptoms of EAE.

Anecdotal support for effectiveness of scorpion sting in rheumatoid arthritis: an autoimmune

disease

60 year old female living in Arizona with arthritis and severe joint pain in the knees. Had taken Clinirol for approximately 20 years, without which mobility was limited due to pain. Was stung by a bark scorpion on inside of left upper leg on February 20, 2006. Sting was extremely painful for the entire day. However, the next day there was no pain and no "tingling". Three days later, patient had no pain in the knees and was able to climb and descend stairs with ease. The beneficial effects lasted about 5-6 weeks. The pain and swelling gradually returned. (Personal communication from patient)

Scorpion-derived peptides blockers of Kv1.3 channels in effector memory T

cells may have use in the treatment of multiple sclerosis, rheumatoid arthritis

and other autoimmune diseases