Fatty Acid Methyl Esters and Solutol HS 15 Confer Neuroprotection after Focal and Global Cerebral Ischemia

Abstract

We previously showed that palmitic methyl ester (PAME) and stearic acid methyl ester (SAME) are simultaneously released from the sympathetic ganglion and PAME possesses potent vasodilatory properties which may be important in cerebral ischemia. Since PAME is a potent vasodilator simultaneously released with SAME, our hypothesis was that PAME/SAME confers neuroprotection in rat models of focal/global cerebral ischemia. We also examined the neuroprotective properties of Solutol HS15, a clinically approved excipient, because it possesses similar fatty acid compositions as PAME/SAME. Asphyxial cardiac arrest (ACA, 6min) was performed 30mins after PAME/SAME treatment (0.02mg/kg, IV). Solutol HS15 (2 ml/kg, IP) was injected chronically for 14 days (once daily). Histopathology of hippocampal CA1 neurons was assessed 7 days after ACA. For focal ischemia experiments, PAME, SAME, or Solutol HS15 was administered following reperfusion after 2 hrs of middle cerebral artery occlusion (MCAO). 2,3,5-triphenyltetrazolium staining of the brain was performed 24hrs after MCAO and the infarct volume was quantified. Following ACA, the number of surviving hippocampal neurons was enhanced by PAME (68%), SAME (69%), and Solutol HS15 (68%)-treated rats as compared to ACA only-treated groups. Infarct volume was decreased by PAME (83%), SAME (68%), and Solutol HS15 (78%) as compared to saline (vehicle) in MCAO-treated animals. PAME, SAME, and Solutol HS15 provide robust neuroprotection in both paradigms of ischemia. This may prove therapeutically beneficial since Solutol HS15 is already administered as a solublizing agent to patients. With proper timing and dosage, administration of Solutol HS15 and PAME/SAME can be an effective therapy against cerebral ischemia.

Physical Exercise Improves Cognitive Outcomes in 2 Models of Transient Cerebral Ischemia

“…Detailed experimental methods including randomization, blinding, and allocation concealment are in Online Supplement (please see http://stroke.ahajournals.org). Focal cerebral ischemia was achieved with intraluminal suture blockage of the middle cerebral artery for 90 minutes 5, 6 . Global cerebral ischemia was induced with 8-minute asphyxia cardiac arrest 5, 7 .…”

Fatty acid methyl esters as a potential therapy against cerebral ischemia

“…The vasodilatory properties of PAME offer a potential therapeutic opportunity in the treatment against cerebral ischemia-induced hypoperfusion consequently promoting brain injury. Pre-treatment with PAME reduced brain infarct volume and neuronal cell death caused by MCAO in the rat (Lin et al, 2014). In addition, pre-treatment with PAME enhanced CBF and brain perfusion 24 h after asphyxial cardiac arrest-induced global ischemia to further attenuate neuronal cell death (Lin et al, 2014) indicating that PAME provides neuroprotection against cerebral ischemia via alleviating hypoperfusion following ischemia.…”

“…Pre-treatment with PAME reduced brain infarct volume and neuronal cell death caused by MCAO in the rat (Lin et al, 2014). In addition, pre-treatment with PAME enhanced CBF and brain perfusion 24 h after asphyxial cardiac arrest-induced global ischemia to further attenuate neuronal cell death (Lin et al, 2014) indicating that PAME provides neuroprotection against cerebral ischemia via alleviating hypoperfusion following ischemia. SAME, a C18:0 saturated fatty acid, was co-released with PAME from SCG and the retina (Lee et al, 2010;Lin et al, 2008).…”

“…These fatty acids are derived from acetyl-CoA with subsequent additions of carbon chains through fatty acid-CoA synthase (Abbadi et al, 2004). Lin et al, 2008Lin et al, , 2014 reported that PAME but not SAME is a vasoactive substance causing vasodilation while SAME is not a vasoactive substance but can provide neuroprotection against ischemia along with PAME in both animal models of global and focal ischemia. It is interesting to note that the synthesis of PA/SA is well-known but the methyl esterification of PA/SA to form PAME/SAME is not prevalent in nature and therefore, not well-understood (Lin and Perez-Pinzon, 2013).…”

“…Only recently has PAME and SAME been presented as a novel component in neuroprotection during cerebral ischemia (Lin and Perez-Pinzon, 2013;Lin et al, 2014). PAME and SAME are simultaneously released from the sympathetic nervous system (Lin et al, 2008).…”