Alpha-Linolenic acid and riluzole treatment confer cerebral protection and improve survival after focal brain ischemia

Abstract

We investigated here the effects of alpha-linolenic acid and riluzole, both activators of the 2P-domain K+ channel family TREK/TRAAK, in a model of focal ischemia clinically relevant to stroke, not only assessing neuronal protection, but also long term survival. Moreover, all the drug treatments were initiated post-ischemia. Mice were subjected to transient middle cerebral artery occlusion (1 h) and reperfusion according to the intraluminal filament model. Drugs were injected into the jugular vein according to three protocols: (i) a single dose of 4 mg/kg riluzole or 500 nmol/kg alpha-linolenic acid at different reperfusion time; (ii) a three-day therapy (a single dose of 2 mg/kg riluzole and 250 nmol/kg alpha-linolenic acid given 1-2, 48 and 72 h after reperfusion); (iii) a three-week therapy (a single dose of 2 mg/kg riluzole and 250 nmol/kg alpha-linolenic acid given once a week during three weeks after reperfusion. A combined treatment with 2mg/kg riluzole+250 nmol/kg alpha-linolenic acid injected 2 h after reperfusion was also tested. A single dose of riluzole (4 mg/kg) or alpha-linolenic acid (500 nmol/kg) injected up to 3 h after reperfusion reduced drastically the stroke volume by 75% and 86%, respectively. Neurological deficits 24 h after ischemia were significantly improved by alpha-linolenic acid500 or riluzole4 with a neurological score of 1.8 as compared with 2.5 observed in vehicle-treated mice. Alpha-linolenic acid- and riluzole treatment were associated with a reduction in cytopathological features of cell injury, including DNA fragmentation and Bax expression in the cortex and the caudate putamen. With regard to the survival rate at 30 days, the best protections were obtained with the alpha-linolenic acid-injection in the three-week therapy as well as with a single dose of the combined treatment (2 mg/kg riluzole+250 nmol/kg alpha-linolenic acid). Palmitic acid, a saturated fatty acid that does not activate the 2P-domain K-channel TREK/TRAAK family, did not provide any neuroprotection. Taken together, these data suggest that the TREK/TRAAK K-channel family may be a promising target for neuroprotection, and that riluzole and alpha-linolenic acid could be of therapeutic value against focal ischemia/reperfusion injury to the brain.

Subchronic Alpha-Linolenic Acid Treatment Enhances Brain Plasticity and Exerts an Antidepressant Effect: A Versatile Potential Therapy for Stroke

“…In the domain of stroke disorders, there is growing evidence that the omega-3 precursor, ALA, is a potent protector in several models of global and focal ischemia (Xiao et al, 1998;Lauritzen et al, 2000;Blondeau et al, 2001Blondeau et al, , 2002Blondeau et al, , 2007Lang-Lazdunski et al, 2003;Heurteaux et al, 2004Heurteaux et al, , 2006a. In a mouse model of stroke, we found that a single injection of ALA, after the onset of stroke, significantly reduced infarct size and improved the neurological score 24-h post-ischemia.…”

“…In a mouse model of stroke, we found that a single injection of ALA, after the onset of stroke, significantly reduced infarct size and improved the neurological score 24-h post-ischemia. Although the single injection of ALA did not improve long-term survival rate, repeated ALA injections over 3 weeks significantly improved survival, suggesting that subchronic ALA treatment triggers other protective pathways (Heurteaux et al, 2006a).…”

Novel neuroprotectant chiral 3-n-butylphthalide inhibits tandem-pore-domain potassium channel TREK-1

“…TREK-1 has been previously reported to play an important role in neuroprotection against acid pathological condi tions [4,7,12,26] . In electrophysiological studies, some lipids substantially increase the probability of these K2P channels being open, thus hyperpolarizing the membrane potential and reducing neuronal excitability [12,[27][28][29][30] . This action on the part of lipids would be predicted to counteract the neuronal damage that arises from the increased membrane excitability that often accompanies CNS insults such as ischemia.…”

Metabolic Risk Factors for Stroke and Transient Ischemic Attacks in Middle-Aged Men

“…␣-linolenic acid has been demonstrated to lower platelet aggregation 25 and to be cross-sectionally related to less carotid artery atherosclerosis, 26 and administration has also been suggested as a promising target for neuroprotection after focal brain ischemia. 27 In summary, the relations of fatty acid patterns to stroke incidence are to some extent still unclear. A weak epidemiological correlation between hypercholesterolemia and increased risk for stroke has been demonstrated.…”