title: Na+/H+ exchanger 1 inhibition reverses manifestation of peripheral diabetic neuropathy in type 1 diabetic rats.
abstract: Evidence for an important role for Na(+)/H(+) exchangers in diabetic complications is emerging. The aim of this study was to evaluate whether Na(+)/H(+) exchanger 1 inhibition reverses experimental peripheral diabetic neuropathy. Control and streptozotocin-diabetic rats were treated with the specific Na(+)/H(+) exchanger 1 inhibitor cariporide for 4 wk after 12 wk without treatment. Neuropathy end points included sciatic motor and sensory nerve conduction velocities, endoneurial nutritive blood flow, vascular reactivity of epineurial arterioles, thermal nociception, tactile allodynia, and intraepidermal nerve fiber density. Advanced glycation end product and markers of oxidative stress, including nitrated protein levels in sciatic nerve, were evaluated by Western blot. Rats with 12-wk duration of diabetes developed motor and sensory nerve conduction deficits, thermal hypoalgesia, tactile allodynia, and intraepidermal nerve fiber loss. All these changes, including impairment of nerve blood flow and vascular reactivity of epineurial arterioles, were partially reversed by 4 wk of cariporide treatment. Na(+)/H(+) exchanger 1 inhibition was also associated with reduction of diabetes-induced accumulation of advanced glycation endproduct, oxidative stress, and nitrated proteins in sciatic nerve. In conclusion, these findings support an important role for Na(+)/H(+) exchanger 1 in functional, structural, and biochemical manifestations of peripheral diabetic neuropathy and provide the rationale for development of Na(+)/H(+) exchanger 1 inhibitors for treatment of diabetic vascular and neural complications.
authors.affiliation: Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Lupachyk
authors.forename: Pierre
authors.initials: P
authors.lastname: Watcho
authors.forename: Hanna
authors.initials: H
authors.lastname: Shevalye
authors.forename: Igor
authors.initials: I
authors.lastname: Vareniuk
authors.forename: Alexander
authors.initials: A
authors.lastname: Obrosov
authors.forename: Irina G
authors.initials: IG
authors.lastname: Obrosova
authors.forename: Mark A
authors.initials: MA
authors.lastname: Yorek
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D001160:Arterioles / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000523:psychology; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009412:Nerve Fibers / Q000502:physiology; D009566:Nitrates / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects; D011765:Pyruvaldehyde / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D058978:Reduced Folate Carrier Protein / Q000037:antagonists & inhibitors*; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism; D012867:Skin / Q000294:innervation; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use*; D013481:Superoxides / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000447:Aldehydes; D001786:Blood Glucose; D017127:Glycation End Products, Advanced; D006146:Guanidines; D009566:Nitrates; D058978:Reduced Folate Carrier Protein; C548700:Slc19a1 protein, mouse; D013450:Sulfones; D013481:Superoxides; C002744:3-nitrotyrosine; D014443:Tyrosine; D011765:Pyruvaldehyde; C093373:cariporide; C027576:4-hydroxy-2-nonenal
keywords: Na+/H+ exchanger-; advanced glycation end product; diabetic peripheral neuropathy; endoneurial blood flow; nerve conduction velocity; vascular reactivity