RGD Reference Report - Inhibiting TRPA1 ion channel reduces loss of cutaneous nerve fiber function in diabetic animals: sustained activation of the TRPA1 channel contributes to the pathogenesis of peripheral diabetic neuropathy. - Rat Genome Database

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Inhibiting TRPA1 ion channel reduces loss of cutaneous nerve fiber function in diabetic animals: sustained activation of the TRPA1 channel contributes to the pathogenesis of peripheral diabetic neuropathy.

Authors: Koivisto, A  Hukkanen, M  Saarnilehto, M  Chapman, H  Kuokkanen, K  Wei, H  Viisanen, H  Akerman, KE  Lindstedt, K  Pertovaara, A 
Citation: Koivisto A, etal., Pharmacol Res. 2012 Jan;65(1):149-58. doi: 10.1016/j.phrs.2011.10.006. Epub 2011 Nov 23.
RGD ID: 10043378
Pubmed: PMID:22133672   (View Abstract at PubMed)
DOI: DOI:10.1016/j.phrs.2011.10.006   (Journal Full-text)

Peripheral diabetic neuropathy (PDN) is a devastating complication of diabetes mellitus (DM). Here we test the hypothesis that the transient receptor potential ankyrin 1 (TRPA1) ion channel on primary afferent nerve fibers is involved in the pathogenesis of PDN, due to sustained activation by reactive compounds generated in DM. DM was induced by streptozotocin in rats that were treated daily for 28 days with a TRPA1 channel antagonist (Chembridge-5861528) or vehicle. Laser Doppler flow method was used for assessing axon reflex induced by intraplantar injection of a TRPA1 channel agonist (cinnamaldehyde) and immunohistochemistry to assess substance P-like innervation of the skin. In vitro calcium imaging and patch clamp were used to assess whether endogenous TRPA1 agonists (4-hydroxynonenal and methylglyoxal) generated in DM induce sustained activation of the TRPA1 channel. Axon reflex induced by a TRPA1 channel agonist in the plantar skin was suppressed and the number of substance P-like immunoreactive nerve fibers was decreased 4 weeks after induction of DM. Prolonged treatment with Chembridge-5861528 reduced the DM-induced attenuation of the cutaneous axon reflex and loss of substance P-like immunoreactive nerve fibers. Moreover, in vitro calcium imaging and patch clamp results indicated that reactive compounds generated in DM (4-hydroxynonenal and methylglyoxal) produced sustained activations of the TRPA1 channel, a prerequisite for adverse long-term effects. The results indicate that the TRPA1 channel exerts an important role in the pathogenesis of PDN. Blocking the TRPA1 channel provides a selective disease-modifying treatment of PDN.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
TRPA1Humandiabetic neuropathy  ISOTrpa1 (Rattus norvegicus) RGD 
Trpa1Ratdiabetic neuropathy  IMP  RGD 
Trpa1Mousediabetic neuropathy  ISOTrpa1 (Rattus norvegicus) RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Trpa1Ratregulation of blood circulation  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Trpa1  (transient receptor potential cation channel, subfamily A, member 1)

Genes (Mus musculus)
Trpa1  (transient receptor potential cation channel, subfamily A, member 1)

Genes (Homo sapiens)
TRPA1  (transient receptor potential cation channel subfamily A member 1)


Additional Information