White matter (WM) damage following a stroke underlies a majority of the neurological disability that is subsequently observed. Although ischemic injury mechanisms are age-dependent, conserving axonal mitochondria provides consistent post-ischemic protection to young and aging WM. Nitric oxide synthase (NOS) activation is a major cause of oxidative and mitochondrial injury in gray matter during ischemia; therefore, we used a pure WM tract, isolated male mouse optic nerve, to investigate whether NOS inhibition provides post-ischemic functional recovery by preserving mitochondria. We show that pan-NOS inhibition applied before oxygen-glucose deprivation (OGD) promotes functional recovery of young and aging axons and preserves WM cellular architecture. This protection correlates with reduced nitric oxide (NO) generation, restored glutathione production, preserved axonal mitochondria and oligodendrocytes, and preserved ATP levels. Pan-NOS inhibition provided post-ischemic protection to only young axons, whereas selective inhibition of NOS3 conferred post-ischemic protection to both young and aging axons. Concurrently, genetic deletion of NOS3 conferred long-lasting protection to young axons against ischemia. OGD upregulated NOS3 levels in astrocytes, and we show for the first time that inhibition of NOS3 generation in glial cells prevents axonal mitochondrial fission and restores mitochondrial motility to confer protection to axons by preserving Miro-2 levels. Interestingly, NOS1 inhibition exerted post-ischemic protection selectively to aging axons, which feature age-dependent mechanisms of oxidative injury in WM. Our study provides the first evidence that inhibition of glial NOS activity confers long-lasting benefits to WM function and structure and suggests caution in defining the role of NO in cerebral ischemia at vascular and cellular levels. White matter (WM) injury during stroke is manifested as the subsequent neurological disability in surviving patients. Aging primarily impacts CNS WM and mechanisms of ischemic WM injury change with age. Nitric oxide is involved in various mitochondrial functions and we propose that inhibition of glia-specific nitric oxide synthase (NOS) isoforms promotes axon function recovery by preserving mitochondrial structure, function, integrity, and motility. Using electrophysiology and three-dimensional electron microscopy, we show that NOS3 inhibition provides a common target to improve young and aging axon function, whereas NOS1 inhibition selectively protects aging axons when applied after injury. This study provides the first evidence that inhibition of glial cell NOS activity confers long-lasting benefits to WM structure and function.

This study tested the hypothesis that the cutaneous vasoconstrictor response to cold is reduced in elderly individuals. We measured laser Doppler flux (LDF) in the fingertip and blood cell velocity (CBV), via videodensitometry, in individual capillaries of the finger nailfold both before and during submersion of the contralateral arm in a 15 degrees C water bath. Subjects were 10 young (M = 25 years) and 10 old (M = 71 years) male adults. During the first minute of cooling, both the young (Y) and old (O) groups experienced a significant (p < .004) decrease in LDF. Over the subsequent 4 minutes of cold stress, LDF remained significantly depressed in the Y group, whereas LDF returned to values not significantly different from pre-cooling control in the O subjects. During the cold stress, CBV significantly decreased in the Y (p < .03) subjects; however, the degree of change was much less than that of LDF (49% decrease in LDF versus 14% decrease for CBV). In contrast to the Y subjects, the O group showed no significant change in CBV during cooling (p > .28). These results indicate that indirect cooling elicits a reflex decrease in cutaneous bloodflow, which is more pronounced in the deep vessels than in the superficial capillaries, and that these effects are attenuated with advancing age.

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