Prolonged infusion of a high dose of kynurenic acid (KYNA) reduces the myelin content in the rat spinal cord with preservation of the axonal integrity and without inducing an inflammatory response. We hypothesized that subdural infusion of a high concentration of KYNA can induce myelin loss in the optic nerves (ONs) of chickens. However, existing methods to deliver agents to the ON are inefficient, unlocalized and provide only acute exposure. Thus, we developed a surgical approach for sustained delivery of KYNA to the chicken ON. In brief, the novel surgical technique, which does not include excision of the extraocular muscles, involves incision of the skin and underlying fascial sheath to access the optic nerve within the muscle cone, implantation of a catheter in the dura of the optic nerve, the other end of which exits the orbit under the skin. The catheter runs under the skin near the lateral canthus, over the ears to the back of the neck, where a second incision is made to both implant the osmotic pump and to attach the catheter to the osmotic pump. India ink was used to confirm prolonged sustained administration to the optic nerves and across the chiasm. This surgical model was used to investigate KYNA\'s effect(s) on myelin loss in the ON. ONs of 7-day old chickens were infused with 50 mM KYNA or phosphate buffered saline (PBS) for seven days. Analysis of KYNA-infused contralateral ON g-ratios and protein levels indicated a reduction in myelin. These findings demonstrate the utility of our surgical approach for sustained delivery of KYNA into the ON and suggest a role for KYNA in modulating CNS myelination.

White matter degeneration is a pathological hallmark of neurodegenerative diseases including Alzheimer\'s. Age remains the greatest risk factor for Alzheimer\'s and the prevalence of age-related late onset Alzheimer\'s is greatest in females. We investigated mechanisms underlying white matter degeneration in an animal model consistent with the sex at greatest Alzheimer\'s risk. Results of these analyses demonstrated decline in mitochondrial respiration, increased mitochondrial hydrogen peroxide production and cytosolic-phospholipase-A2 sphingomyelinase pathway activation during female brain aging. Electron microscopic and lipidomic analyses confirmed myelin degeneration. An increase in fatty acids and mitochondrial fatty acid metabolism machinery was coincident with a rise in brain ketone bodies and decline in plasma ketone bodies. This mechanistic pathway and its chronologically phased activation, links mitochondrial dysfunction early in aging with later age development of white matter degeneration. The catabolism of myelin lipids to generate ketone bodies can be viewed as a systems level adaptive response to address brain fuel and energy demand. Elucidation of the initiating factors and the mechanistic pathway leading to white matter catabolism in the aging female brain provides potential therapeutic targets to prevent and treat demyelinating diseases such as Alzheimer\'s and multiple sclerosis. Targeting stages of disease and associated mechanisms will be critical.