The Inhibitory Effects of Cobalt Protoporphyrin IX and Cannabinoid 2 Receptor Agonists in Type 2 Diabetic Mice.

Abstract

The activation of the transcription factor Nrf2 inhibits neuropathy and modulates the activity of delta-opioid receptors (DOR) in type 2 diabetic mice but the impact of Nrf2/HO-1 pathway on the antinociceptive actions of cannabinoid 2 receptors (CB2R) has not been assessed. Using male mice BKS.Cg-m+/+Leprdb/J (db/db) we investigated if treatment with cobalt protoporphyrin IX (CoPP), an HO-1 inductor, inhibited mechanical allodynia, hyperglycemia and obesity associated to type 2 diabetes. The antinociceptive effects of JWH-015 and JWH-133 (CB2R agonists) administered with and without CoPP or sulforaphane (SFN), a Nrf2 transcription factor activator, have been also evaluated. The expression of Nrf2, HO-1, NAD(P)H: quinone oxidoreductase 1 (NQO1) and c-Jun N-terminal kinase (JNK) in sciatic nerve and that of the CB2R on the dorsal root ganglia from animals treated with CoPP and/or SFN were assessed. CoPP treatment inhibited allodynia, hyperglycemia and body weight gain in db/db mice by enhancing HO-1/NQO1 levels and reducing JNK phosphorylation. Both CoPP and SFN improved the antiallodynic effects of JWH-015 and JWH-133 and expression of CB2R in db/db mice. Therefore, we concluded that the activation of antioxidant Nrf2/HO-1 pathway potentiate the effects of CB2R agonists and might be suitable for the treatment of painful neuropathy linked to type 2 diabetes.

• Authors: Christina McDonnell, Sergi Leánez, Olga Pol
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 18 Issue 11 (Oct 28 2017) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 29143802 (Publication Type: Journal Article)

Chemical References

• Blood Glucose
• Cannabinoid Receptor Agonists
• Cannabinoids
• NF-E2-Related Factor 2
• Protoporphyrins
• Receptor, Cannabinoid, CB2
• cobaltiprotoporphyrin
• Heme Oxygenase-1
• 1,1-dimethylbutyl-1-deoxy-Delta(9)-THC

Topics

• Animals
• Blood Glucose (drug effects)
• Body Weight (drug effects)
• Cannabinoid Receptor Agonists (pharmacology)
• Cannabinoids (pharmacology)
• Diabetes Mellitus, Experimental
• Diabetes Mellitus, Type 2 (drug therapy, metabolism)
• Diabetic Neuropathies (drug therapy, metabolism)
• Disease Models, Animal
• Ganglia, Spinal (drug effects, metabolism)
• Heme Oxygenase-1 (metabolism)
• Hyperalgesia (drug therapy, etiology)
• Male
• Mice
• Mice, Transgenic
• NF-E2-Related Factor 2 (metabolism)
• Protoporphyrins (pharmacology)
• Receptor, Cannabinoid, CB2 (agonists)
• Sciatic Nerve (metabolism)