Thursday, May 31, 2012
Figure 1. PDN: a sodium channel bound to excite. According to a study in Nature Medicine,
methylglyoxal (MG) modifies sodium channel NaV1.8 (PN3; SCN10A) in nociceptive neurons to cause
thermal and mechanical hypersensitivity in the extremities of patients with
hyperglycemia raises plasma levels of the metabolite MG [a] that
accumulates in nociceptive and other peripheral neurons [b], which express
only low levels of glyoxalase 1 (GLO1). The enzyme is required to convert MG
nociceptive neurons, MG binds the intracellular portion (inactivation gate) of
NaV1.8 [c] and induces unknown structural modifications that inhibit the
channel's ability to close in response to increases in the cell's membrane
increase allows thermal and mechanical stimuli [d] to induce excessive
sodium influx [e], resulting in excessive neuronal firing [f]
that causes pain [g], even in response to stimuli that are not painful
in healthy individuals.
Z123212 (Z212), a small molecule that blocks NaV1.7 (SCN9A) and NaV1.8 sodium channels from Zalicus Inc., is in
preclinical development to treat chronic inflammatory and neuropathic pain.