Cannabidiol protects retinal neurons by preserving glutamine synthetase activity in diabetes.
OBJECTIVE
We have previously shown that non-psychotropic cannabidiol (CBD) protects retinal neurons in diabetic rats by inhibiting reactive oxygen species and blocking tyrosine nitration. Tyrosine nitration may inhibit glutamine synthetase (GS), causing glutamate accumulation and leading to further neuronal cell death. We propose to test the hypothesis that diabetes-induced glutamate accumulation in the retina is associated with tyrosine nitration of GS and that CBD treatment inhibits this process.


METHODS
Sprague Dawley rats were made diabetic by streptozotocin injection and received either vehicle or CBD (10 mg/kg/2 days). After eight weeks, retinal cell death, Müller cell activation, GS tyrosine nitration, and GS activity were determined.


RESULTS
Diabetes causes significant increases in retinal oxidative and nitrative stress compared with controls. These effects were associated with Müller cell activation and dysfunction as well as with impaired GS activity and tyrosine nitration of GS. Cannabidiol treatment reversed these effects. Retinal neuronal death was indicated by numerous terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL)-labeled cells in diabetic rats compared with untreated controls or CBD-treated rats.


CONCLUSIONS
These results suggest that diabetes-induced tyrosine nitration impairs GS activity and that CBD preserves GS activity and retinal neurons by blocking tyrosine nitration.
El-Remessy
A B
AB
Clinical and Experimental Therapeutics, University of Georgia, Augusta, GA 30912, USA. aelremessy@mcg.edu
Khalifa
Y
Y
Ola
S
S
Ibrahim
A S
AS
Liou
G I
GI
D000818:Animals; D002185:Cannabidiol / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism*; D008297:Male; D009457:Neuroglia / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D015538:Nitrosation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D055351:Retinal Neurons / Q000201:enzymology* / Q000473:pathology*
D018696:Neuroprotective Agents; D002185:Cannabidiol; D053148:Caspase 3; D005974:Glutamate-Ammonia Ligase
Hepatology. 2005 May;41(5):1065-73
15830392
Psychopharmacology (Berl). 1979 Aug 8;64(2):243-6
115049
Diabetologia. 2005 Feb;48(2):351-60
15688208
J Neurochem. 2002 Feb;80(3):448-56
11905991
Am J Pathol. 2003 Jun;162(6):1995-2004
12759255
Exp Eye Res. 2000 Jun;70(6):723-30
10843776
Invest Ophthalmol Vis Sci. 2008 Dec;49(12):5526-31
18641283
Free Radic Biol Med. 2006 Oct 15;41(8):1191-6
17015165
Invest Ophthalmol Vis Sci. 2010 Mar;51(3):1765-72
19875652
Int J Mol Med. 2008 Jun;21(6):667-76
18506358
J Neurochem. 1980 Apr;34(4):866-72
6102113
Eur J Pharmacol. 2000 Jun 9;398(1):139-46
10856458
Pharmacology. 1980;21(3):175-85
7413719
J Pharmacol Exp Ther. 2010 Jan;332(1):125-34
19815813
J Neurochem. 1999 Jun;72(6):2506-15
10349861
Diabetes. 2003 Feb;52(2):506-11
12540628
Pharmacotherapy. 2009 Feb;29(2):182-92
19170588
Curr Eye Res. 2009 Sep;34(9):727-36
19839866
J Biol Chem. 2007 Apr 27;282(17):12467-74
17324929
Neurochem Int. 2001 Apr;38(5):385-90
11222918
Diabetes Metab Res Rev. 2009 Oct;25(7):678-86
19685553
Science. 1993 Oct 29;262(5134):689-95
7901908
Trends Neurosci. 1996 Aug;19(8):312-8
8843599
Neurochem Res. 2009 Feb;34(2):244-54
18563560
Cell Tissue Res. 2009 Mar;335(3):477-88
19156441
Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):2784-9
9501167
FEBS Lett. 2007 Jan 9;581(1):84-90
17174954
Diabetes. 2002 Jan;51(1):198-203
11756341
Am J Pathol. 2010 Sep;177(3):1187-97
20651233
J Neurochem. 2002 Mar;80(5):771-9
11948240
Invest Ophthalmol Vis Sci. 2007 Nov;48(11):5152-9
17962468
Mol Cell Proteomics. 2008 May;7(5):864-74
18165258
J Neuroimmunol. 1997 Feb;72(2):169-77
9042110
Neurosci Lett. 2003 Jul 31;346(1-2):61-4
12850548
Mol Vis. 2008;14:2190-203
19052649
Invest Ophthalmol Vis Sci. 2009 Apr;50(4):1778-90
19098320
J Physiol. 2008 Sep 15;586(18):4401-8
18565995
Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8268-73
9653176
Eur Rev Med Pharmacol Sci. 2007 May-Jun;11(3):155-63
17970231
Diabetes. 1998 May;47(5):815-20
9588455
J Neurochem. 1997 Dec;69(6):2312-25
9375662
J Clin Invest. 1998 Aug 15;102(4):783-91
9710447
Curr Eye Res. 2000 Oct;21(4):814-9
11120572
Diabetes. 2002 Jul;51(7):2241-8
12086956
Am J Pathol. 2003 Nov;163(5):1997-2008
14578199
J Cell Sci. 2005 Jan 1;118(Pt 1):243-52
15615788
Am J Pathol. 2006 Jan;168(1):235-44
16400026
Invest Ophthalmol Vis Sci. 2002 Sep;43(9):3109-16
12202536
Exp Eye Res. 2009 Dec;89(6):967-71
19699197
Diabetes. 2008 Apr;57(4):889-98
18285558
Expert Opin Pharmacother. 2006 Apr;7(5):607-15
16553576
Arch Ophthalmol. 1997 Sep;115(9):1161-6
9298058