Bimoclomol (BRLP-42) Ameliorates Peripheral Neuropathy in Streptozotocin-Induced Diabetic Rats

Biró, Katalin T.; Jednákovits, Andrea; Kukorelli, T; Hegedüs, Erzsébet; Korányi, László

doi:10.1016/s0361-9230(97)00118-4

Cited by 50 publications

(13 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This small difference between the useful and toxic effects, however, makes the clinical use of canavanine as a drug to prevent diabetic retinopathy unlikely. Recently, the beneficial effects in diabetic wound healing and neuropathy of a molecular chaperone coinducer were reported [8,9]. Our results are in agreement with the conclusions of these reports and prompt further investigations for the use of amino acid analogues other than canavanine and other nontoxic stress protein inducers in easing the chronic consequences of diabetes such as retinopathy.…”

Section: Discussionsupporting

confidence: 90%

“…Recent reports established the chaperone coinducer Bimoclomol as a potent compound that induces acceleration of diabetic wound healing and slowing of diabetic neuropathy [8,9]. Based on these results, as a continuation of our initial studies to characterize changes in molecular chaperones in diabetic animals [10,11], the present work analyses the effect of a well-known inducer of molecular chaperones, canavanine [12][13][14][15][16][17], on diabetic retinopathy.…”

mentioning

confidence: 94%

See 1 more Smart Citation

Attenuation of diabetic retinopathy by the molecular chaperone-inducer amino acid analogue canavanine in streptozotocin-diabetic rats

Kálmán

Tóth

Szlavik

et al. 1998

CMLS, Cell. Mol. Life Sci.

View full text Add to dashboard Cite

The effect of canavanine treatment on the electroretinograms of healthy and streptozotocin-diabetic rats was studied. The characteristic amplitudes of the a-wave, W2 and W3 oscillatory potentials were markedly diminished in the 2-week streptozotocin-diabetic rats compared with those of the control rats. In contrast, the amplitudes of all the responses of the canavanine-pretreated streptozotocin-diabetic rats were practically indistinguishable from those of the control animals. Our results prompt further investigations for the use of amino acid analogues and other inducers of molecular chaperones in easing the chronic consequences of diabetes such as retinopathy.

show abstract

Section: Discussionsupporting

confidence: 90%

mentioning

confidence: 94%

Attenuation of diabetic retinopathy by the molecular chaperone-inducer amino acid analogue canavanine in streptozotocin-diabetic rats

Kálmán

Tóth

Szlavik

et al. 1998

CMLS, Cell. Mol. Life Sci.

View full text Add to dashboard Cite

show abstract

“…For example, N-terminal Hsp90 inhibitors decreased motor neuron degeneration in a murine model of spinal and bulbar muscular atrophy (Waza et al, 2005) and reduced aggregated or hyperphosphorylated forms of tau protein in JNPL3 mice (Luo et al, 2007) and humanized tau protein transgenic mice (Dickey et al, 2007). Similarly, induction of Hsp70 with HSF1 activators (bimoclomol and related hydroxylamine derivatives) improved insulin resistance (Chung et al, 2008), diabetic wound healing (Atalay et al, 2009; Vigh et al, 1997) and was sufficient to prevent the slowing of NCV in diabetic rats (Biro et al, 1997). In the present study, we provide the first evidence that a novel C-terminal Hsp90 inhibitor that increases Hsp70 expression is similarly effective in preventing death of unmyelinated neurons, demyelination of myelinated sensory neurons and was able to reverse pre-existing sensory deficits associated with the development of DPN in mice.…”

Section: Discussionmentioning

confidence: 99%

Inhibiting Heat-Shock Protein 90 Reverses Sensory Hypoalgesia in Diabetic Mice

Urban

et al. 2010

ASN Neuro

133

View full text Add to dashboard Cite

Increasing the expression of Hsp70 (heat-shock protein 70) can inhibit sensory neuron degeneration after axotomy. Since the onset of DPN (diabetic peripheral neuropathy) is associated with the gradual decline of sensory neuron function, we evaluated whether increasing Hsp70 was sufficient to improve several indices of neuronal function. Hsp90 is the master regulator of the heat-shock response and its inhibition can up-regulate Hsp70. KU-32 (N-{7-[(2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2-yloxy]-8-methyl-2-oxo-2H-chromen-3-yl}acetamide) was developed as a novel, novobiocin-based, C-terminal inhibitor of Hsp90 whose ability to increase Hsp70 expression is linked to the presence of an acetamide substitution of the prenylated benzamide moiety of novobiocin. KU-32 protected against glucose-induced death of embryonic DRG (dorsal root ganglia) neurons cultured for 3 days in vitro. Similarly, KU-32 significantly decreased neuregulin 1-induced degeneration of myelinated Schwann cell DRG neuron co-cultures prepared from WT (wild-type) mice. This protection was lost if the co-cultures were prepared from Hsp70.1 and Hsp70.3 KO (knockout) mice. KU-32 is readily bioavailable and was administered once a week for 6 weeks at a dose of 20 mg/kg to WT and Hsp70 KO mice that had been rendered diabetic with streptozotocin for 12 weeks. After 12 weeks of diabetes, both WT and Hsp70 KO mice developed deficits in NCV (nerve conduction velocity) and a sensory hypoalgesia. Although KU-32 did not improve glucose levels, HbA1c (glycated haemoglobin) or insulin levels, it reversed the NCV and sensory deficits in WT but not Hsp70 KO mice. These studies provide the first evidence that targeting molecular chaperones reverses the sensory hypoalgesia associated with DPN.

show abstract

“…There is great interest in developing new agents capable of reducing both IR and complications of diabetes. BRX‐220, a hydroxylamine derivative and a member of the BRX family, was developed by Biorex as a follow‐up compound of bimoclomol (BML)2,3 against diabetic complications and IR. BRX‐220 proved to be effective in diabetic small‐fiber sensory neuropathy and neuroregeneration,4 as well as in high‐fat diet‐induced IR of rats12 after long‐term oral treatment.…”

Section: Introductionmentioning

confidence: 99%

“…Insulin resistance (IR) has a main causal role in the development of several diseases, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] for example, dyslipidemia, hypertension, atherosclerosis, and type 2 diabetes. 11 Type 2 diabetes mellitus is a common, underdiagnosed, and largely incurable condition associated with a number of serious complications, for example, neuropathy, retinopathy, and nephropathy.…”

Section: Introductionmentioning

confidence: 99%

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

Kürthy¹,

Mogyorósi²,

Nagy³

et al. 2002

Annals of the New York Academy of Sciences

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Bimoclomol (BRLP-42) Ameliorates Peripheral Neuropathy in Streptozotocin-Induced Diabetic Rats

Cited by 50 publications

References 25 publications

Attenuation of diabetic retinopathy by the molecular chaperone-inducer amino acid analogue canavanine in streptozotocin-diabetic rats

Attenuation of diabetic retinopathy by the molecular chaperone-inducer amino acid analogue canavanine in streptozotocin-diabetic rats

Inhibiting Heat-Shock Protein 90 Reverses Sensory Hypoalgesia in Diabetic Mice

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

Contact Info

Product

Resources

About