Rationale:Neurogenic hypertension is characterized by an increase in sympathetic activity and often resistance to drug treatments. We previously reported that it is also associated with a reduction ...of angiotensin-converting enzyme type 2 (ACE2) and an increase in a disintegrin and metalloprotease 17 (ADAM17) activity in experimental hypertension. In addition, while multiple cells within the central nervous system have been involved in the development of neurogenic hypertension, the contribution of ADAM17 has not been investigated.Objective:To assess the clinical relevance of this ADAM17-mediated ACE2 shedding in hypertensive patients and further identify the cell types and signaling pathways involved in this process.Methods and Results:Using a mass spectrometry-based assay, we identified ACE2 as the main enzyme converting angiotensin II into angiotensin-(1–7) in human cerebrospinal fluid. We also observed an increase in ACE2 activity in the cerebrospinal fluid of hypertensive patients, which was correlated with systolic blood pressure. Moreover, the increased level of tumor necrosis factor-α in those cerebrospinal fluid samples confirmed that ADAM17 was upregulated in the brain of hypertensive patients. To further assess the interaction between brain renin–angiotensin system and ADAM17, we generated mice lacking angiotensin II type 1 receptors specifically on neurons. Our data reveal that despite expression on astrocytes and other cells types in the brain, ADAM17 upregulation during deoxycorticosterone acetate–salt hypertension occurs selectively on neurons, and neuronal angiotensin II type 1 receptors are indispensable to this process. Mechanistically, reactive oxygen species and extracellular signal-regulated kinase were found to mediate ADAM17 activation.Conclusions:Our data demonstrate that angiotensin II type 1 receptors promote ADAM17-mediated ACE2 shedding in the brain of hypertensive patients, leading to a loss in compensatory activity during neurogenic hypertension.
Fenofibrate (FF) is a common lipid-lowering drug and a potent agonist of the peroxisome proliferator-activated receptor alpha (PPARα). FF and several other agonists of PPARα have interesting ...anticancer properties, and our recent studies demonstrate that FF is very effective against tumor cells of neuroectodermal origin. In spite of these promising anticancer effects, the molecular mechanism(s) of FF-induced tumor cell toxicity remains to be elucidated. Here we report a novel PPARα-independent mechanism explaining FF's cytotoxicity in vitro and in an intracranial mouse model of glioblastoma. The mechanism involves accumulation of FF in the mitochondrial fraction, followed by immediate impairment of mitochondrial respiration at the level of complex I of the electron transport chain. This mitochondrial action sensitizes tested glioblastoma cells to the PPARα-dependent metabolic switch from glycolysis to fatty acid β-oxidation. As a consequence, prolonged exposure to FF depletes intracellular ATP, activates the AMP-activated protein kinase-mammalian target of rapamycin-autophagy pathway, and results in extensive tumor cell death. Interestingly, autophagy activators attenuate and autophagy inhibitors enhance FF-induced glioblastoma cytotoxicity. Our results explain the molecular basis of FF-induced glioblastoma cytotoxicity and reveal a new supplemental therapeutic approach in which intracranial infusion of FF could selectively trigger metabolic catastrophe in glioblastoma cells.
Alzheimer’s disease (AD) is a uniquely human, age-related central nervous system (CNS) disorder for which there is no adequate experimental model. While well over 100 transgenic murine models of AD ...(TgAD) have been developed that recapitulate many of the neuropathological features of AD, key pathological features of AD such as progressive neuronal atrophy, neuron cell loss, and neurofibrillary tangle (NFT) formation have not been observed in any TgAD model to date. To more completely analyze and understand the neuropathology, altered neuro-inflammatory and innate-immune signaling pathways, and the complex molecular-genetics and epigenetics of AD, it is therefore necessary to rigorously examine short post-mortem interval (PMI) human brain tissues to gain a deeper and more thorough insight into the neuropathological mechanisms that characterize the AD process. This perspective-methods paper will highlight some important recent findings on the utilization of short PMI tissues in sporadic (idiopathic; of unknown origin) AD research with focus on the extraction and quantification of RNA, and in particular microRNA (miRNA) and messenger RNA (mRNA) and analytical strategies, drawing on the authors’ combined 125 years of laboratory experience into this investigative research area. We sincerely hope that new investigators in the field of “gene expression analysis in neurological disease” will benefit from the observations presented here and incorporate these recent findings and observations into their future experimental planning and design.
BACKGROUND:Diabetes mellitus affects 9.3% of the US population and increases risks of surgery and complications. Diabetic neuropathic pain (DNP), one of the main consequences of diabetes mellitus, is ...extremely difficult to treat. Current medications yield limited benefits and/or have severe adverse effects. Therefore, new, effective treatment is needed.
METHODS:Streptozotocin at 55 mg/kg was injected intraperitoneally in rats to induce diabetes mellitus. Diabetic rats exhibiting neuropathic pain underwent intrathecal injection of purified agrin proteins at various doses and were then tested for tactile allodynia to evaluate whether DNP was inhibited. The agrin effects were also analyzed with patch-clamp recording on spinal cord slices.
RESULTS:Fifty–kilo Dalton agrin (Agr50) at 0.2 and 2 ng suppressed DNP when given intrathecally, while 25- and 75-kDa agrin (Agr25, Agr75) had little effect. The suppressive effect of Agr50 lasted 4 hours after a single bolus injection. The difference in effects of Agr50 on mean withdrawal threshold (4.6 ± 2.2 g before treatment to 26 ± 0 g after treatment) compared with that of Agr25 (4.9 ± 2.0 g to 4.9 ± 2.0 g) and Agr75 (5.3 ± 2.3 g to 9.2 ± 2.5 g) was highly significant (P < .01). On spinal cord slices, Agr50 increased spontaneous GABAergic current activities, suggesting increased spontaneous inhibitory postsynaptic currents and action potential firing rate from GABA neurons, whereas Agr25 and Agr75 had no such effect.
CONCLUSIONS:Agr50 had a potent suppressive effect on DNP and increased spontaneous inhibitory postsynaptic currents and action potential firing rate from GABA neurons. Therefore, Agr50 may provide a potential therapy for DNP.
The effect of intoxicating substances on assessment of Glasgow Coma Scale (GCS) in the trauma setting has not been completely elucidated.
A trauma registry was queried for patients with blunt head ...trauma in 2013–2017. Initial GCS score and toxicology screening from the database were reviewed. Next recorded GCS score from the neurosurgery evaluation and change in GCS score (ΔGCS) were compared.
We reviewed 468 patients. In 217 (46.4%) patients, no toxic substances were found, whereas >1 toxic substance was found in 104 (22.2%) patients. Alcohol level above the legal limit was found in 109 (23.3%) patients, marijuana was found in 105 (22.4%) patients, benzodiazepines were found in 94 (20.1%) patients, opiates were found in 48 (10.3%) patients, and cocaine was found in 41 (8.8%) patients. Mean change in GCS score was significantly higher in impaired patients compared with patients with a negative screening test (1.74 ± 2.4 vs. 0.75 ± 2.7, P < 0.001); this is despite both groups having a similar initial GCS score (6.23 ± 3.86 in impaired group vs. 6.47 ± 3.52 in sober group, P = 0.677). Initial GCS score was 3 in 187 patients, of whom 150 had a positive toxicology screen. Change in GCS score was significantly higher in the impaired group (2.75 ± 2.7 vs. 1.19 ± 1.8, P < 0.001).
Intoxicating substances can confound GCS assessment in trauma patients. This can have effects on patient care as well as performance metrics and predictive analytics. These patients should be screened, and intoxicating substances should be reversed or allowed to wear off before GCS score is recorded for benchmarking or quality reporting.
Neurogenic hypertension is characterized by an increase in sympathetic activity and often resistance to drug treatments. We previously reported that it is also associated with a reduction of ...angiotensin-converting enzyme type 2 (ACE2) and an increase in a disintegrin and metalloprotease 17 (ADAM17) activity in experimental hypertension. In addition, while multiple cells within the central nervous system have been involved in the development of neurogenic hypertension, the contribution of ADAM17 has not been investigated.
To assess the clinical relevance of this ADAM17-mediated ACE2 shedding in hypertensive patients and further identify the cell types and signaling pathways involved in this process.
Using a mass spectrometry-based assay, we identified ACE2 as the main enzyme converting angiotensin II into angiotensin-(1-7) in human cerebrospinal fluid. We also observed an increase in ACE2 activity in the cerebrospinal fluid of hypertensive patients, which was correlated with systolic blood pressure. Moreover, the increased level of tumor necrosis factor-α in those cerebrospinal fluid samples confirmed that ADAM17 was upregulated in the brain of hypertensive patients. To further assess the interaction between brain renin-angiotensin system and ADAM17, we generated mice lacking angiotensin II type 1 receptors specifically on neurons. Our data reveal that despite expression on astrocytes and other cells types in the brain, ADAM17 upregulation during deoxycorticosterone acetate-salt hypertension occurs selectively on neurons, and neuronal angiotensin II type 1 receptors are indispensable to this process. Mechanistically, reactive oxygen species and extracellular signal-regulated kinase were found to mediate ADAM17 activation.
Our data demonstrate that angiotensin II type 1 receptors promote ADAM17-mediated ACE2 shedding in the brain of hypertensive patients, leading to a loss in compensatory activity during neurogenic hypertension.
Abstract only INTRODUCTION: Vasospasm following aneurysmal subarachnoid hemorrhage is a very extensively studied source of morbidity and mortality. Numerous treatment regiments have been investigated ...and published. A recently published article discussed the use of prolonged infusion of verapamil through an indwelling catheter as an effective treatment for medically refractory severe vasospasm. The goal of our study is to report our institution's experience with this method of treatment. METHODS & MATERIALS: All patients with medically refractory vasospasm from July 2009 through August 2011 were included in the study. A retrospective review of data was compiled. In particular, age, sex, aneurysm location, aneurysm treatment, intra-arterial treatment fo vasospasm, dosages and times of medication infusion, and presence of new ischemia or progression of ischemia on CT scan were investigated. RESULTS: A total of 13 treatments were administered. Nicardipine was used in two treatments, and verapamil was used in the remaining eleven treatments. The doses of nicardipine were 10mg and 49 mg, and were infused over 20 min and 75 min respectively. The doses of verapamil ranged from 41 mg to 200 mg. One patient was treated with both nicardipine and verapamil at one treatment session. The infusion times ranged from 25 min to 22 hr. Between 1 and 3 vessels were treated per patient resulting in a total of 19 vessels treated. The number of treatments per patient ranged from one to two. Review of pre- and post-treatment CT scans revealed worsening of ischemic changes in 9 of the 13 treatments, while the remaining 4 treatments showed no change or progression of ischemic changes on imaging. One patient had a conversion to a hemorrhagic infarct from an inschemic infarct after a treatment. CONCLUSIONS: Upon reviewing our data we have come to the conclusion that prolonged infusion of calcium channel blockers is not an effective treatment for medically refractory severe vasospasm. After 13 treatments we have decided to not continue with this treatment. Therefore, we believe that angioplasty is still the gold standard for treatment of medically refractory vasospasm.
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