linoleic-acid and Demyelinating-Diseases

Microglia play a critical role in the clearance of myelin debris, thereby ensuring functional recovery from neural injury. Here, using mouse model of demyelination following two-point LPC injection, we show that the microglial autophagic-lysosomal pathway becomes overactivated in response to severe demyelination, leading to lipid droplet accumulation and a dysfunctional and pro-inflammatory microglial state, and finally failed myelin debris clearance and spatial learning deficits. Data from genetic approaches and pharmacological modulations, via microglial Atg5 deficient mice and intraventricular BAF A1 administration, respectively, demonstrate that staged suppression of excessive autophagic-lysosomal activation in microglia, but not sustained inhibition, results in better myelin debris degradation and exerts protective effects against demyelination. Combined multi-omics results in vitro further showed that enhanced lipid metabolism, especially the activation of the linoleic acid pathway, underlies this protective effect. Supplementation with conjugated linoleic acid (CLA), both in vivo and in vitro, could mimic these effects, including attenuating inflammation and restoring microglial pro-regenerative properties, finally resulting in better recovery from demyelination injuries and improved spatial learning function, by activating the peroxisome proliferator-activated receptor (PPAR-γ) pathway. Therefore, we propose that pharmacological inhibition targeting microglial autophagic-lysosomal overactivation or supplementation with CLA could represent a potential therapeutic strategy in demyelinated disorders.

Topics: Animals; Autophagy; Demyelinating Diseases; Linoleic Acid; Mice; Microglia; Regeneration

The authors investigated whether fatty acid emulsion affects the blood-brain barrier (BBB), whether disrupted BBB is reversible, and whether the fatty acid emulsion technique may be a model for BBB research.. The fat emulsion was made with 0.05 mL of oleic acid or linoleic acid and 20 mL of normal saline. The internal carotid artery in 14 cats was infused with oleic acid emulsion (group 1) and with linoleic acid emulsion in 12 cats (group 2). Gd-enhanced T1-weighted (Gd-T1WI), diffusion-weighted (DWI), and additional apparent diffusion coefficient (ADC) map magnetic resonance imaging (MRI) was obtained at 1 hour, 1 and 4 days, and 1 week after infusion. MRI findings were evaluated qualitatively. Quantitatively, the signal intensity ratio (SIR) of the lesion to the contralateral hemisphere was measured on Gd-T1WIs. The SIRs were statistically analyzed using the student t test. The brain tissue was removed immediately for light and electron microscopy examination if the lesion showed no contrast enhancement and was isointense on DWIs and the ADC maps.. The lesions appeared at 1 hour in both groups as contrast enhancement on Gd-T1WIs, as isointensity or mild hyperintensity on DWIs, and as isointensity on the ADC maps. On day 1, these MRI findings were decreased in group 1 and were not seen in group 2. At 1 hour, the SIRs of group 1 were significantly higher than those of group 2 (P = 0.016). On day 1, the SIRs of both groups approximated 1.0. Light microscopy findings revealed minor necrosis and demyelination in one cat from group 1 and in 3 cats from group 2. Electron microscopy examinations showed minimal findings in the cortical lesions in groups 1 and 2.. Infusion of unsaturated fatty acid emulsion into the carotid artery of cats revealed vasogenic edema of the brain and reversible changes as depicted on MRI. This unsaturated fat emulsion technique may be used as a model for research on BBB disruption.

Topics: Animals; Blood-Brain Barrier; Brain; Brain Edema; Carotid Artery, Internal; Cats; Demyelinating Diseases; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Emulsions; Gadolinium DTPA; Image Enhancement; Injections, Intra-Arterial; Linoleic Acid; Necrosis; Oleic Acid; Time Factors