Editorial of Special Issue: Blood-CNS and Blood-Nerve Barriers in Health and Diseases and Potential Therapy

The blood–brain barrier (BBB) and blood–nerve barrier (BNB) play crucial roles in maintaining homeostasis of the central nervous system (CNS) and peripheral nervous system (PNS), respectively. Disruptions in these barriers are associated with multiple disorders of the CNS and PNS. With respect to the blood-CNS barriers, this Special Issue, “Blood-CNS and Blood-Nerve Barriers in Health and Diseases and Potential Therapy” highlights novel therapeutic approaches targeting the neurovascular units of these barriers to treat stroke and dementia, explores the neurovascular aspects between traumatic brain injury (TBI) and dementia, and examines the roles of microRNAs (miRNAs) in multiple neurological disorders.

Compared to the BBB, the BNB is less well characterized. This Special Issue includes reviews describing the normal structure and function of the BNB and our current understanding of the alterations in BNB structure and function in various neuropathic disorders particularly those that are inflammatory or nociceptive in nature. Besides specialized endothelium lining the neurovasculature, specialized covering (perineurium) wrapping individual nerve fascicles may also contribute to BNB function. BNB has spatial variations and the blood-dorsal root ganglion-barrier (BDB) exemplifies regional variations in this barrier’s structure and function. Articles in the BNB section allude to the potential of developing therapeutic approaches enhancing or relaxing restrictive properties of the BNB for the treatment of specific neuropathic conditions, by modulating endoneurial influx of cellular and/or non-cellular inflammatory effectors, and drug delivery especially for chronic neuropathic pain, respectively.

Among nine articles presented in the issue, six articles focus on the Blood-CNS barrier including three articles focusing on stroke. Stroke is a major cause of death and a leading cause of disability in the United States and throughout the world. The majority of strokes are caused by vessel occlusion leading to ischemia. Subsequent reperfusion often causes damage beyond the initial neuronal loss caused by ischemia. This reperfusion-mediated damage is associated with a disruption of the BBB. Due to multi-factorial pathophysiological mechanisms of stroke injury, the Stroke Treatment Academic Industry Roundtable (STAIR) recommends that stroke therapies emphasize treatments targeting multiple mechanisms of action and pathways.

The focus of the review by Boese, Lee, and Hamblin (Boese et al., 2020c) is peroxisome proliferator-activated receptor-alpha (PPARα), which has been gaining attention as a therapeutic target in modulating stroke pathophysiology. Through multiple mechanisms, activating PPARα may be neuroprotective and reduce damage associated with ischemic stroke. Several of these mechanisms relate to the preservation of the BBB by PPARα agonists, suggesting that existing ligands or novel ligands could be beneficial in treating ischemic stroke patients. However, the authors note that sex-dependent differences need to be considered when designing preclinical studies and clinical trials.

Thromboembolic stroke is a type of ischemic stroke that is caused by release of a thrombus from an atherosclerotic plaque in the carotid artery, an atheroma in the aortic arch, or the heart. Common to these is the presence of platelets, which serve as a source of neutrophil-recruiting chemokines. Accumulating evidence suggests that infiltration of neutrophils from the periphery during the acute stroke phase contributes to post-stroke injury. Stamatovic, Phillips, Keep, and Andjelkovic (Stamatovic et al., 2020) assessed the effect of redirecting neutrophil migration by peripherally implanting a neutrophil attractant chemokine CXCL1-soaked sponge. In a mouse model of thromboembolic stroke induced by the injection of a suspension of platelets and fibrin, the authors showed that peripheral increase of CXCL1 reduced neutrophil recruitment into the brain and stroke lesion volume, decreased mortality, and improved the neurological scores post-stroke.

From a clinical standpoint, the use of tissue plasminogen activator (tPA) within 4.5 hours of ischemic stroke onset improves clinical outcome. However, delayed tPA administration can increase reperfusion damage. Stem cell therapy, especially neural stem cells, offers great promise in treating stroke (Huang et al., 2014; Lee et al., 2007). The findings by Boese, Eckert, Hamblin, and Lee (Boese et al., 2020a) demonstrated the role of NSCs to limit neurovascular injury post-stroke. Authors used an experimental stroke model in aged mice and administered tPA 6 hours after vessel occlusion. Injection of human NSCs 24 hours after vessel occlusion reduced infarct size and inflammation while ameliorating BBB disruption and increasing the level of brain-derived neurotrophic factor. These findings highlight therapeutic applications of NSCs as “by-stander” cells that can ameliorate detrimental effects of delayed tPA treatment.

Multiple therapeutic mechanisms of NSCs were also highlighted in the review by Boese, Hamblin, and Lee (Boese et al., 2020b), focusing on neurovascular damage as a contributing factor in dementia. Indeed, disruption of BBB function has been proposed as an early event in Alzheimer’s Disease (AD). The review introduces the pathophysiology of AD, provides an overview of NSC biology, and describes the preclinical studies supporting the application of NSCs for treating AD. The authors emphasize the challenges in translating such preclinical studies into humans, because the available animal models do not represent the diversity of the AD patient population.

TBI and dementia are both associated with the accumulation of aggregation-prone proteins, such as amyloid-β (Aβ) and phosphorylated tau. Furthermore, both are associated with impairment or dysfunction of the BBB. The relationship between TBI, damage to the BBB, and dementia is explored in the review by Abrahamson and Ikonomivic (Abrahamson and Ikonomovic, 2020) in which they present studies involving human subjects or autopsy tissue, along with studies using animal models.

The last article on the CNS barrier topic reviews the roles of microRNAs (miRNAs), small non-coding RNA molecules, in regulating BBB integrity. Ma, Zhang, and Yin (Ma et al., 2020) outline the multiple miRNAs and their diverse targets implicated in neurological disorders that have a BBB disruption component. The conditions include those involving the BBB and the blood-spinal cord barrier and feature ischemic and hemorrhagic stroke, brain tumors, cerebral infections, traumatic brain and spinal cord injuries, dementia, and autoimmune neurodegenerative disease.

Three articles in the issue focus on the peripheral BNB. The monograph by Ubogu (Ubogu, 2020) provides a comprehensive overview of the BNB at structural, cellular, and molecular levels in health and disease, particularly highlighting findings from studies on human neuropathies. Pathophysiological alterations in the endoneurial microvascular endothelial compartment of the BNB in various inflammatory (e.g., Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy) and infectious (e.g., human immunodeficiency virus) neuropathies and chronic neuropathic pain are reviewed. Recent transcriptomics and proteomics findings are also discussed, which have significantly advanced the understanding of BNB composition and function in health and alteration of this complex multicellular system in peripheral neuropathies and chronic neuropathic pain. A sub-theme of the review is normal and altered leukocyte trafficking across the BNB in health and disease, respectively, which could be a target of therapeutic manipulation in disease states.

Reinhold and Rittner (Reinhold and Rittner, 2020) review the constitution of the perineurium and its role in BNB function. The authors emphasize the importance of tight junctions and the molecular composition of these cell-cell adhesions in shaping the functional and morphological properties of the BNB both along peripheral nerves and in the sensory dorsal root ganglion (DRG) at the BDB. Notably, the BDB is heterogenous within neuron-rich or nerve fiber-rich areas of the DRGs. Various experimental approaches targeting perineurial relaxation for drug delivery in animal models are also reviewed. Arguably, better mechanistic characterization and understanding of how the BNB (perineurial and endothelial components) and BDB are altered by neuropathic injury and/or pain in animal models will enable development of novel therapeutic approaches for conditions such as sickle cell disease, diabetic neuropathy, and GBS.

Stubbs (Stubbs, 2020) reviews emerging experimental approaches targeting the endothelial and extraendothelial components of the BNB to enhance or transiently relax integrity of its barrier functions. Enhancing BNB integrity is particularly relevant for immune-mediated neuropathies and theoretically, it could reduce endoneurial burden of cellular and soluble mediators of inflammation and nerve injury. Conversely, transient relaxation of the BNB could allow targeted drug delivery for the management of chronic intractable pain. A potential extension of such an approach is endoneurial delivery of neuroprotective and/or proregenerative drugs to prevent nerve injury and enhance repair. The article highlights that despite preclinical advancements identifying potential targets and approaches of modifying BNB function, there is a lag in clinical adaptation of emerging experimental findings.

Collectively, these articles show that disruptions in the barriers between the circulatory system and the nervous system are involved in various neurological disorders and support research endeavors investigating their physiological and pathophysiological roles. A common thread was that barrier disruption is accompanied by increased inflammation, resulting in a cascade of detrimental events that eventually lead to tissue compromise and long-term disability. Experimental approaches manipulating the compliance (rigidity or laxity) of blood-neural barriers are emerging. One hopes that in the future these strategies can be harnessed for spatiotemporal adjustment of BBB and BNB stringency to fine tune injury-related neural inflammation and spatially controlled delivery of cellular and noncellular therapeutics. The development of novel noninvasive biological markers assessing the integrity of the BBB and BNB in real time can expedite the clinical translation of experimental strategies targeting blood-neural barrier(s) for therapeutics, i.e., modulation of inflammation and drug delivery. We hope that this Special Issue will inspire more research on the BBB and BNB leading to novel options for treating neurovascular, neuroinflammatory, and neurodegenerative diseases.