Effect of BRX‐220 against Peripheral Neuropathy and Insulin Resistance in Diabetic Rat Models

Abstract

Bimoclomol (BML), a symptomatic antidiabetic agent, has been developed by Biorex R & D Co. to treat diabetic neuropathy and retinopathy. BRX‐220, an orally active member of the BRX family, has been developed to treat diabetic complications and insulin resistance (IR) as a follow‐up compound. The effect of BRX‐220 on peripheral neuropathy was examined in rats with diabetes (type 1) induced by administration of a β‐cell toxin, streptozotocin (STZ, 45 mg/kg iv). Nerve functions were evaluated by electrophysiological measurements of muscle motor and sensory nerve conduction velocities (MNCV and SNCV, respectively). MNCV and SNCV decreased in diabetic rats by 25% (p < 0.001). A 1‐month preventive treatment with BRX‐220 (2.5, 5, 10, and 20 mg/kg po) dose‐dependently improved diabetes‐related deficits in MNCV (51.3%, 71.3%, 86.1%, and 91.3%) and SNCV (48.9%, 68.5%, 86.1%, and 93.2%). Insulin sensitivity was measured using the insulin tolerance test (ITT), both in STZ diabetic and in Zucker diabetic fatty (ZDF) rats (model of type 2 diabetes). Severe IR was detected in STZ diabetic and ZDF rats. This resistance was significantly (p < 0.05) reduced by BRX‐220 treatment.

Targeting Molecular Chaperones in Diabetic Peripheral Neuropathy

“…Therefore, despite the non-linear pattern of changing in HSP expression, the data suggest a possible inverse relationship between the level of HSP and neuropathological change in DM. Consistent with this notion, compounds known to co-induce HSP were able to improve diabetic peripheral neuropathy (Kurthy et al, 2002) and wound healing (Vigh et al, 1997). Although the development of diabetic complications is associated with a progressive decline in the expression of HSPs, mice with a genetic knock-out of the inducible isoforms of HSP70 (HSP70.1 and 70.3) did not develop any more severe neurophysiological deficits than were observed in wild-type diabetic mice (Urban et al, 2010).…”

“…Indeed, pharmacological induction of HSP70 with the hydroxylamine derivative BGP-15, -lipoic acid or GGA improved glucose tolerance in insulin-resistant mice (Chung et al, 2008), rats (Gupte et al, 2009a) and monkeys (Kavanagh et al, 2011), respectively. Notably, administration of a HSP co-inducer BRX-220 to STZ-diabetic rats dose-dependently reduced insulin resistance and was associated with improved peripheral sensory and motor nerve deficits (Kurthy et al, 2002). In Gupte's study of rats fed with high-fat diet, addition of an HSP70 inhibitor diminished the heat-induced JNK depression, indicating that inhibition of JNK activation by heat-shock is largely HSP70-dependent (Gupte et al, 2009b).…”

“…To date, most relevant evidence is largely correlative in nature and comes from indirect evaluation of pharmacological HSP coinducers. In STZ-induced diabetic Wistar rats, two known HSP co-inducing compounds, bimoclomol (Biro et al, 1997) and BRX-220 (Kurthy et al, 2002), independently reversed the slowing of motor and sensory conduction deficits as well as the ischemic conduction failure in sciatic nerve. Substantially advancing these findings, studies in our laboratory also demonstrated a potent reversal of pre-existing mechanical and thermal hypoalgesia in addition to an improved motor and sensory NCV in STZ-mice administered a small molecule HSP90 inhibitor, KU-32 (Urban et al, 2010).…”

Diabetic Peripheral Neuropathy: Should a Chaperone Accompany Our Therapeutic Approach?

“…For example, patients with type 2 diabetes experienced reductions in blood glucose concentration and symptomatic neuropathy after receiving regular hot-tub treatment (Hooper, 1999(Hooper, , 2003. In diabetic rats, the HSF1 activators bimoclomol and arimoclomol (BRX-220) improved diabetic wound healing and nerve conduction deficits, respectively (Vígh et al, 1997;Kü rthy et al, 2002); direct HSF1 activators may provide another pharmacologic route to modulating genes that express chaperones and antioxidant proteins (Neef et al, 2011). The potential effectiveness of ␣-lipoic acid in treating DPN has already been noted and ␣-lipoic acid therapy has been normalized.…”

The Heat Shock Connection of Metabolic Stress and Dietary Restriction

“…More importantly, a 41°C heat treatment once a week for 12 weeks improved glucose tolerance and reduced stress-activated signaling in rats fed by a high-fat diet suggesting a crosstalk between the development of HSF1 dependent thermotolerance and metabolic stress tolerance [41]. The chaperone coinducer bimoclomol derivative, BRX-220 was also able to improve insulin sensitivity of both Zucker fatty diabetic rats, and streptozotocin-treated diabetic rats [42]. Finally, a recent study demonstrated that besides heat shock either overexpression or pharmacologic induction of Hsp70 by a novel chaperone co-inducer BGP-15 was sufficient to prevent the development of obesity-induced insulin resistance in fat-fed mice [43].…”