Targeting type-2 metabotropic glutamate receptors to protect vulnerable hippocampal neurons against ischemic damage.
BACKGROUND
To examine whether metabotropic glutamate (mGlu) receptors have any role in mechanisms that shape neuronal vulnerability to ischemic damage, we used the 4-vessel occlusion (4-VO) model of transient global ischemia in rats. 4-VO in rats causes a selective death of pyramidal neurons in the hippocampal CA1 region, leaving neurons of the CA3 region relatively spared. We wondered whether changes in the expression of individual mGlu receptor subtypes selectively occur in the vulnerable CA1 region during the development of ischemic damage, and whether post-ischemic treatment with drugs targeting the selected receptor(s) affords neuroprotection.


RESULTS
We found that 4-VO caused significantly reduction in the transcript of mGlu2 receptors in the CA1 region at times that preceded the anatomical evidence of neuronal death. Down-regulation of mGlu2 receptors was associated with reduced H3 histone acetylation at the Grm2 promoter. The transcripts of other mGlu receptor subtypes were unchanged in the CA1 region of 4-VO rats. Ischemia did not cause changes in mGlu2 receptor mRNA levels in the resistant CA3 region, which, interestingly, were lower than in the CA1 region. Targeting the mGlu2 receptors with selective pharmacologic ligands had profound effects on ishemic neuronal damage. Post-ischemic oral treatment with the selective mGlu2 receptor NAM (negative allosteric modulator), ADX92639 (30 mg/kg), was highly protective against ischemic neuronal death. In contrast, s.c. administration of the mGlu2 receptor enhancer, LY487379 (30 mg/kg), amplified neuronal damage in the CA1 region and extended the damage to the CA3 region.


CONCLUSIONS
These findings suggest that the mGlu2 receptor is an important player in mechanisms regulating neuronal vulnerability to ischemic damage, and that mGlu2 receptor NAMs are potential candidates in the experimental treatments of disorders characterized by brain hypoperfusion, such as hypovolemic shock and cardiac arrest.
Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, 86077, Pozzilli, Italy.
Marta
M
Motolese
Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, 86077, Pozzilli, Italy.
Federica
F
Mastroiacovo
Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, 86077, Pozzilli, Italy.
Milena
M
Cannella
Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, 86077, Pozzilli, Italy.
Domenico
D
Bucci
Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, 86077, Pozzilli, Italy.
Anderson
A
Gaglione
Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, 86077, Pozzilli, Italy.
Barbara
B
Riozzi
Addex Therapeutics, Plan-les-Ouates, Geneva, Switzerland.
Robert
R
Lütjens
Addex Therapeutics, Plan-les-Ouates, Geneva, Switzerland.
Sonia M
SM
Poli
Addex Therapeutics, Plan-les-Ouates, Geneva, Switzerland.|Present address: Pragma Therapeutics, 74166, Saint-Julien-en-Genevois, France.
Sylvain
S
Celanire
Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, 86077, Pozzilli, Italy.|Department of Physiology and Pharmacology, Sapienza University of Rome, Piazzale Aldo Moro, 5, 00185, Rome, Italy.
Valeria
V
Bruno
Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, 86077, Pozzilli, Italy.
Giuseppe
G
Battaglia
Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, 86077, Pozzilli, Italy. ferdinandonicoletti@hotmail.com.|Department of Physiology and Pharmacology, Sapienza University of Rome, Piazzale Aldo Moro, 5, 00185, Rome, Italy. ferdinandonicoletti@hotmail.com.
Ferdinando
F
Nicoletti
D000107:Acetylation / Q000187:drug effects; D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology*; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000473:pathology; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects; D020869:Gene Expression Profiling; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D008024:Ligands; D008297:Male; D058990:Molecular Targeted Therapy; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D000066829:Neuroprotection / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation / Q000235:genetics
D006657:Histones; D008024:Ligands; C476436:N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; D013449:Sulfonamides; C108822:metabotropic glutamate receptor 2; D056464:Histone Deacetylase 2