White matter (WM) occupies a large volume of the human cerebrum and is mainly composed of myelinated axons and myelin-producing glial cells. The myelinated axons within WM are the structural foundation for efficient neurotransmission between cortical and subcortical areas. Similar to neuron-enriched gray matter areas, WM undergoes a series of changes during the process of aging. WM malfunction can induce serious neurobehavioral and cognitive impairments. Thus, age-related changes in WM may contribute to the functional decline observed in the elderly. In addition, aged WM becomes more susceptible to neurological disorders, such as stroke, traumatic brain injury (TBI), and neurodegeneration. In this review, we summarize the structural and functional alterations of WM in natural aging and speculate on the underlying mechanisms. We also discuss how age-related WM changes influence the progression of various brain disorders, including ischemic and hemorrhagic stroke, TBI, Alzheimer’s disease, and Parkinson’s disease. Although the physiology of WM is still poorly understood relative to gray matter, WM is a rational therapeutic target for a number of neurological and psychiatric conditions.

Recent advances in stroke reperfusion therapies have led to remarkable improvement in clinical outcomes, but many patients remain severely disabled, due in part to the lack of effective neuroprotective strategies. In this review, we show that 95% of published preclinical studies on "neuroprotectants" (1990-2018) reported positive outcomes in animal models of ischemic stroke, while none translated to successful Phase III trials. There are many complex reasons for this failure in translational research, including that the majority of clinical trials did not test early delivery of neuroprotectants in combination with successful reperfusion. In contrast to the clinical trials, >80% of recent preclinical studies examined the neuroprotectant in animal models of transient ischemia with complete reperfusion. Furthermore, only a small fraction of preclinical studies included long-term functional assessments, aged animals of both genders, and models with stroke comorbidities. Recent clinical trials demonstrate that 70%-80% of patients treated with endovascular thrombectomy achieve successful reperfusion. These successes revive the opportunity to retest previously failed approaches, including cocktail drugs that target multiple injury phases and different cell types. It is our hope that neurovascular protectants can be retested in future stroke research studies with specific criteria outlined in this review to increase translational successes.

Regulatory T cells (Tregs) are known to protect against ischemic stroke. However, the low frequency of Tregs restricts their clinical utility. This study investigated whether expanding the number of Tregs in vivo with the IL-2/IL-2 antibody complex (IL-2/IL-2Ab) could improve stroke outcomes and further elaborated the mechanisms of protection in male mice. C57BL/6 mice received IL-2/IL-2Ab or isotype IgG (IsoAb) intraperitoneally for 3 d before (pretreatment) or starting 2 h after (posttreatment) 60 min middle cerebral artery occlusion (MCAO). IL-2/IL-2Ab selectively increased the number of Tregs in the blood, spleen, and lymph nodes. The IL-2/IL-2Ab treatment significantly reduced infarct volume, inhibited neuroinflammation, and improved sensorimotor functions, as manifested by rotarod test and foot fault test, compared with IsoAb-treated stroke mice. Treg depletion was then achieved by diphtheria toxin (DT) injection into transgenic mice expressing the DT receptor under the control of the Foxp3 promoter (DTR mice). The depletion of Tregs completely eliminated IL-2/IL-2Ab-afforded neuroprotection. Interestingly, adoptive transfer of Tregs collected from IL-2/IL-2Ab-treated mice demonstrated more potent neuroprotection than an equal number of Tregs prepared from IsoAb-treated mice, suggesting that IL-2/IL-2Ab not only elevated Treg numbers, but also boosted their functions. Mechanistically, IL-2/IL-2Ab promoted the expression of CD39 and CD73 in expanded Tregs. CD73 deficiency diminished the protective effect of IL-2/IL-2Ab-stimulated Tregs in stroke mice. The results show that IL-2/IL-2Ab expands Tregs in vivo and boosts their immunomodulatory function. The activation of CD39/CD73 signaling in Tregs may participate as a potential mechanism underlying IL-2/IL-2Ab-afforded neuroprotection against ischemic brain injury.

White matter injury induced by ischemic stroke elicits sensorimotor impairments, which can be further deteriorated by persistent proinflammatory responses. We previously reported that delayed and repeated treatments with omega-3 polyunsaturated fatty acids (n-3 PUFAs) improve spatial cognitive functions and hippocampal integrity after ischemic stroke. In the present study, we report a post-stroke n-3 PUFA therapeutic regimen that not only confers protection against neuronal loss in the gray matter but also promotes white matter integrity. Beginning 2 hours after 60 minutes of middle cerebral artery occlusion (MCAO), mice were randomly assigned to receive intraperitoneal docosahexaenoic acid (DHA) injections (10 mg/kg, daily for 14 days), alone or in combination with dietary fish oil (FO) supplements starting 5 days after MCAO. Sensorimotor functions, gray and white matter injury, and microglial responses were examined up to 28 days after MCAO. Our results showed that DHA and FO combined treatment facilitated long-term sensorimotor recovery and demonstrated greater beneficial effect than DHA injections alone. Mechanistically, n-3 PUFAs not only offered direct protection on white matter components, such as oligodendrocytes, but also potentiated microglial M2 polarization, which may be important for white matter repair. Notably, the improved white matter integrity and increased M2 microglia were strongly linked to the mitigation of sensorimotor deficits after stroke upon n-3 PUFA treatments. Together, our results suggest that post-stroke DHA injections in combination with FO dietary supplement benefit white matter restoration and microglial responses, thereby dictating long-term functional improvements.

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