As human life expectancy rises, the aged population will increase. Aging is accompanied by changes in tissue structure, often resulting in functional decline. For example, aging within blood vessels contributes to a decrease in blood flow to important organs, potentially leading to organ atrophy and loss of function. In the central nervous system, cerebral vascular aging can lead to loss of the integrity of the blood-brain barrier, eventually resulting in cognitive and sensorimotor decline. One of the major of types of cognitive dysfunction due to chronic cerebral hypoperfusion is vascular cognitive impairment and dementia (VCID). In spite of recent progress in clinical and experimental VCID research, our understanding of vascular contributions to the pathogenesis of VCID is still very limited. In this review, we summarize recent findings on VCID, with a focus on vascular age-related pathologies and their contribution to the development of this condition.

Recombinant tissue plasminogen activator (tPA) is a Food and Drug Administration-approved thrombolytic treatment for ischemic stroke. tPA is also naturally expressed in glial and neuronal cells of the brain, where it promotes axon outgrowth and synaptic plasticity. However, there are conflicting reports of harmful versus neuroprotective effects of tPA in acute brain injury models. Furthermore, its impact on white matter integrity in preclinical traumatic brain injury (TBI) has not been thoroughly explored, although white matter disruption is a better predictor of long-term clinical outcomes than focal lesion volumes. Here we show that the absence of endogenous tPA in knockout mice impedes long-term recovery of white matter and neurological function after TBI. tPA-knockout mice exhibited greater asymmetries in forepaw use, poorer sensorimotor balance and coordination, and inferior spatial learning and memory up to 35 d after TBI. White matter damage was also more prominent in tPA knockouts, as shown by diffusion tensor imaging, histological criteria, and electrophysiological assessments of axon conduction properties. Replenishment of tPA through intranasal application of the recombinant protein in tPA-knockout mice enhanced neurological function, the structural and functional integrity of white matter, and postinjury compensatory sprouting in corticofugal projections. tPA also promoted neurite outgrowth in vitro, partly through the epidermal growth factor receptor. Both endogenous and exogenous tPA protected against white matter injury after TBI without increasing intracerebral hemorrhage volumes. These results unveil a previously unappreciated role for tPA in the protection and/or repair of white matter and long-term functional recovery after TBI.

Emerging evidence suggests that tissue plasminogen activator (tPA), currently the only FDA-approved medication for ischemic stroke, exerts important biological actions on the CNS besides its well-known thrombolytic effect. In this study, we investigated the role of tPA on primary neurons in culture and on brain recovery and plasticity after ischemic stroke in mice. Treatment with recombinant tPA stimulated axonal growth in culture, an effect independent of its protease activity and achieved through epidermal growth factor receptor (EGFR) signaling. After permanent focal cerebral ischemia, tPA knockout mice developed more severe sensorimotor and cognitive deficits and greater axonal and myelin injury than wild-type mice, suggesting that endogenously expressed tPA promotes long-term neurological recovery after stroke. In tPA knockout mice, intranasal administration of recombinant tPA protein 6 hours poststroke and 7 more times at 2 d intervals mitigated white matter injury, improved axonal conduction, and enhanced neurological recovery. Consistent with the proaxonal growth effects observed in vitro, exogenous tPA delivery increased poststroke axonal sprouting of corticobulbar and corticospinal tracts, which might have contributed to restoration of neurological functions. Notably, recombinant mutant tPA-S478A lacking protease activity (but retaining the EGF-like domain) was as effective as wild-type tPA in rescuing neurological functions in tPA knockout stroke mice. These findings demonstrate that tPA improves long-term functional outcomes in a clinically relevant stroke model, likely by promoting brain plasticity through EGFR signaling. Therefore, treatment with the protease-dead recombinant tPA-S478A holds particular promise as a neurorestorative therapy, as the risk for triggering intracranial hemorrhage is eliminated and tPA-S478A can be delivered intranasally hours after stroke.

Objective. The aim of the study was to explore the regularity of acupoints in the treatment of amyotrophic lateral sclerosis (ALS) by means of data mining technology. Methods. Nine databases, including SinoMed, Chongqing VIP (CQVIP), China National Knowledge Infrastructure (CNKI), Wanfang Data, Cochrane Library, PubMed, MEDLINE, Web of Science, and Embase, were comprehensively searched till December 2021. The published clinical literature testing acupuncture in the treatment of ALS was eligible for inclusion. Studies were organized to establish the prescription database. Modular data mining analysis, including acupoint frequency, complex network analysis, association rule analysis, and cluster analysis were used to conduct statistical analysis. Results. Forty-two literature studies on 141 acupoints were included, involving 626 times the total application frequency. The top 5 acupoints in application frequency were Hegu (LI 4, 67%), Zusanli (ST 36, 67%), Quchi (LI 11, 52%), Sanyinjiao (SP 6, 48%), and Yanglingquan (GB 34, 45%). The most involved meridian was the large intestine meridian of hand Yangming (90 times). The generally used acupoints were mainly distributed in the lower limbs. The top 5 combinations in application frequency were Hegu-Quchi (75 times), Quchi-Zusanli (66 times), Zusanli-Sanyinjiao (54 times), Hegu-Sanyinjiao (54 times), and Quchi-Sanyinjiao (49 times). The acupoint combinations with the strongest association were Quchi, Hegu, Zusanli, Sanyinjiao, and Shousanli (LI 10). There were 7 acupoint groups according to the cluster analysis. The core prescriptions were Hegu, Zusanli, Quchi, and Jiaji (EX-B 2). Conclusions. Hegu, Zusanli, Quchi, and Jiaji could be used as the main prescriptions in treating ALS. The combination of Quchi, Hegu, Zusanli, and Sanyinjiao should be selected with priority in acupuncture therapy.