Soluble epoxide hydrolase (sEH) degrades epoxides of fatty acids including epoxyeicosatrienoic acid isomers (EETs), which are produced as metabolites of the cytochrome P450 branch of the arachidonic acid pathway. EETs exert a variety of largely beneficial effects in the context of inflammation and vascular regulation. sEH inhibition is shown to be therapeutic in several cardiovascular and renal disorders, as well as in peripheral analgesia, via the increased availability of anti-inflammatory EETs. The success of sEH inhibitors in peripheral systems suggests their potential in targeting inflammation in the central nervous system (CNS) disorders. Here, we describe the current roles of sEH in the pathology and treatment of CNS disorders such as stroke, traumatic brain injury, Parkinson's disease, epilepsy, cognitive impairment, dementia and depression. In view of the robust anti-inflammatory effects of stem cells, we also outlined the potency of stem cell treatment and sEH inhibitors as a combination therapy for these CNS disorders. This review highlights the gaps in current knowledge about the pathologic and therapeutic roles of sEH in CNS disorders, which should guide future basic science research towards translational and clinical applications of sEH inhibitors for treatment of neurological diseases.

Every year, approximately 1.4 million US citizens visit emergency rooms for traumatic brain injuries. Formerly known as an acute injury, chronic neurodegenerative symptoms such as compromised motor skills, decreased cognitive abilities, and emotional and behavioral changes have caused the scientific community to consider chronic aspects of the disorder. The injury causing impact prompts multiple cell death processes, starting with neuronal necrosis, and progressing to various secondary cell death mechanisms. Secondary cell death mechanisms, including excitotoxicity, oxidative stress, mitochondrial dysfunction, blood–brain barrier disruption, and inflammation accompany chronic traumatic brain injury (TBI) and often contribute to long-term disabilities. One hallmark of both acute and chronic TBI is neuroinflammation. In acute stages, neuroinflammation is beneficial and stimulates an anti-inflammatory response to the damage. Conversely, in chronic TBI, excessive inflammation stimulates the aforementioned secondary cell death. Converting inflammatory cells from pro-inflammatory to anti-inflammatory may expand the therapeutic window for treating TBI, as inflammation plays a role in all stages of the injury. By expanding current research on the role of inflammation in TBI, treatment options and clinical outcomes for afflicted individuals may improve. This paper is a review article. Referred literature in this paper has been listed in the references section. The data sets supporting the conclusions of this article are available online by searching various databases, including PubMed. Some original points in this article come from the laboratory practice in our research center and the authors’ experiences.

Objectives:To test the hypothesis that increased aortic stiffening is associated with greater cerebrospinal fluid (CSF) evidence of core Alzheimer’s disease pathology (Aβ, phosphorylated tau (p-tau)), neurodegeneration (total tau (t-tau)), synaptic dysfunction (neurogranin), neuroaxonal injury (neurofilament light (NFL)), and neuroinflammation (YKL-40, sTREM2), we analyzed pulse wave velocity (PWV) data and CSF data among older adults.Methods:Participants free of stroke and dementia from the Vanderbilt Memory and Aging Project, an observational community-based study, underwent cardiac magnetic resonance to assess aortic pulse wave velocity (PWV, m/sec) and lumbar puncture to obtain CSF. Linear regressions related aortic PWV to CSF Aβ, p-tau, t-tau, neurogranin, NFL, YKL-40, and sTREM2 concentrations adjusting for age, race/ethnicity, education, apolipoprotein (APOE) ε4 status, Framingham Stroke Risk Profile, and cognitive diagnosis. Models were repeated testing PWV interactions with age, diagnosis, APOE-ε4, and hypertension on each biomarker.Results:146 participants were examined (72±6 years). Aortic PWV interacted with age on p-tau (β=0.31, p=0.04), t-tau, (β=2.67, p=0.05), neurogranin (β=0.94, p=0.04), and sTREM2 (β=20.4, p=0.05). Among participants over age 73 years, higher aortic PWV related to higher p-tau (β=2.4, p=0.03), t-tau (β=19.3, p=0.05), neurogranin (β=8.4, p=0.01), and YKL-40 concentrations (β=7880, p=0.005). Aortic PWV had modest interactions with diagnosis on neurogranin (β=-10.76, p=0.03) and hypertension status on YKL-40 (β=-18020, p<0.001).Conclusions:Among our oldest participants, age 74 years and older, greater aortic stiffening is associated with in vivo biomarker evidence of neuroinflammation, tau phosphorylation, synaptic dysfunction, and neurodegeneration, but not amyloidosis. Central arterial stiffening may lead to cumulative cerebral microcirculatory damage and blood flow delivery to tissue, resulting in neuroinflammation and neurodegeneration in more advanced age.

Stem cell transplantation is historically understood as a powerful preclinical therapeutic following stroke models. Current clinical strategies including clot busting/retrieval are limited by their time windows (tissue plasminogen activator: 3–4 h) and inevitable reperfusion injuries. However, 24+ h post-stroke, stem cells reduce infarction size, improve neurobehavioral performance, and reduce inflammatory agents including interleukins. Typically, interleukin-6 (IL-6) is regarded as proinflammatory, and thus, preclinical studies often discuss it as beneficial for neurological recuperation when stem cells reduce IL-6′s expression. However, some studies have also demonstrated neurological benefit with upregulation of IL-6 or preconditioning of stem cells with IL-6. This review specifically focuses on stem cells and IL-6, and their occasionally disparate, occasionally synergistic roles in the setting of ischemic cerebrovascular insults.

Introduction Neonatal traumatic brain injury (TBI) is a significant cause of developmental disorders. Autologous stem cell therapy may enhance neonatal brain plasticity towards repair of the injured neonatal brain. Areas Covered The endogenous neonatal anti-inflammatory response can be enhanced by biological treatments. Stem cell therapy stands as a robust approach for sequestering the inflammation-induced cell death in the injured brain. Here, we discuss the use of umbilical cord blood cells and bone marrow stromal cells for acute and chronic treatment of experimental neonatal TBI. Autologous stem cell transplantation may retard and possibly even halt this neuroinflammation-plagued secondary cell death. Clinical translation of this stem cell therapy will require identifying the therapeutic window post-injury and harvesting ample supply of transplantable autologous stem cells. Stem cell banking with access to cryopreserved cells may allow readily available transplantable cells in addressing the unpredictable nature of neonatal TBI. Harnessing the anti-inflammatory properties of stem cells is key in combating the progressive neurodegeneration after the initial injury. Expert Opinion Combination treatments, such as with hypothermia, may enhance the therapeutic effects of stem cells. Stem cell therapy has potential as stand-alone or adjunctive therapy for treating neuroinflammation associated with acute and progressive stages of neonatal TBI.

The field of stem cell therapy is growing rapidly and hopes to offer an alternative solution to diseases that are historically treated medically or surgically. One such focus of research is the treatment of medically refractory epilepsy, which is traditionally approached from a surgical or interventional standpoint. Research shows that stem cell transplantation has potential to offer significant benefits to the epilepsy patient by reducing seizure frequency, intensity, and neurological deficits that often result from the condition. This review explores the basic science progress made on the topic of stem cells and epilepsy by focusing on experiments using animal models and highlighting the most recent developments from the last 4 years.

Background Blood‐brain barrier (BBB) permeability has been implicated in Alzheimer’s disease and is associated with decreased cerebral blood flow and cognitive impairment. However, associations between BBB permeability and structural brain changes remain unknown. This study relates the cerebrospinal fluid (CSF)/plasma albumin ratio, a proxy measure for BBB permeability, to grey matter volumes and white matter integrity Method Vanderbilt Memory and Aging Project participants free of clinical dementia or stroke (n=148, 72±6 years, 41% female, 32% apolipoprotein E (APOE) ε4 positive) underwent fasting lumbar puncture for CSF sampling and blood draw for plasma sampling. Participants underwent 3T T1‐weighted imaging to quantify grey matter volumes and diffusion tensor imaging (DTI) to quantify white matter integrity. Voxel‐wise analyses using non‐parametric permutations cross‐sectionally related the CSF/plasma albumin ratio to DTI metrics, adjusting for demographic and health variables, diagnosis, and APOE‐ε4 status. Linear regressions related the CSF/plasma albumin ratio to grey matter volumes, adjusting for identical covariates plus intracranial volume. Follow‐up models tested interactions with APOE‐ε4 status. Result In the entire sample, the CSF/plasma albumin ratio was unrelated to grey matter volumes and white matter integrity (p‐values>0.28) but interacted with APOE‐ε4 status on total grey matter (p‐value=0.02), frontal lobe (p‐value=0.01), and occipital lobe volumes (p‐value=0.04). Stratification suggested a higher CSF/plasma albumin ratio, indicating impaired BBB function, related to smaller grey matter volumes among APOE‐ε4 carriers. The CSF/plasma albumin ratio also interacted with APOE‐ε4 status on white matter integrity in the temporal and frontal lobes (p‐values<0.05), with associations present in APOE‐ε4 non‐carriers. Conclusion Increased BBB permeability is associated with decreased grey matter volume in APOE‐ε4 carriers, specifically in the frontal and occipital lobes. APOE‐ε4 may act as a vascular modifier in these regions, such that increased BBB permeability exacerbates underlying neurotoxicity and neurodegeneration. In contrast, the association between increased BBB permeability and compromised white matter integrity is driven by APOE‐ε4 non‐carriers. Taken together, these results suggest that BBB permeability may be an etiology of neurodegeneration in APOE‐ε4 carriers and highlight the importance of APOE‐ε4 status when studying BBB effects on brain health.