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Antioxidants (Basel, Switzerland) May 2024Hypertension reduces the bioavailability of vascular nitric oxide (NO) and contributes to the onset of vascular dementia (VaD). A loss of NO bioavailability increases...
2-(4-Methylthiazol-5-yl) Ethyl Nitrate Hydrochloride Ameliorates Cognitive Impairment via Modulation of Oxidative Stress and Nuclear Factor Kappa B (NF-κB) Signaling Pathway in Chronic Cerebral Hypoperfusion-Associated Spontaneously Hypertensive Rats.
Hypertension reduces the bioavailability of vascular nitric oxide (NO) and contributes to the onset of vascular dementia (VaD). A loss of NO bioavailability increases inflammation and oxidative stress. 2-(4-Methylthiazol-5-yl) ethyl nitrate hydrochloride (W1302) is a novel nitric oxide donor (NOD) which is undergoing phase I clinical trials in China for the treatment of VaD. In this study, we investigated the protective effects of W1302 in VaD rats induced by the permanent occlusion of a bilateral common carotid arteries model related to spontaneous hypertension (SHR-2VO), and we further explored the underlying mechanisms. Nimodipine was used as a positive control. Our results showed that W1302 treatment for 4 weeks (10 mg/Kg/day) exhibited stronger improvement in the spatial learning and memory deficits in SHR-2VO rats compared with nimodipine with slightly lower systolic blood pressure (SBP). Meanwhile, W1302 treatment significantly increased NO and cGMP production, restored mitochondrial membrane potential and attenuated oxidative stress as evidenced by increasing ATP production and reducing malondialdehyde (MDA) levels in the brain. Furthermore, W1302 treatment markedly inhibited the iNOS activity and decreased TNF-α expression via inhibiting the nuclear factor kappa B (NF-κB) signaling pathway. Nimodipine treatment also restored these aberrant changes, but its ATP production was weaker than that of W1302, and there was no significant effect on NO release. Taken together, W1302 exhibited beneficial effects on complications in VaD with hypertension, which is involved in suppressing oxidative damage, and the inflammatory reaction might be mediated by an increase in NO release. Therefore, W1302 has therapeutic potential for the treatment of VaD caused by chronic cerebral hypoperfusion-associated spontaneous hypertension.
PubMed: 38790690
DOI: 10.3390/antiox13050585 -
Cureus Mar 2024This report describes the case of an 18-year-old Micronesian pregnant woman at 32 weeks gestation, initially presumed to have eclampsia but later diagnosed with...
This report describes the case of an 18-year-old Micronesian pregnant woman at 32 weeks gestation, initially presumed to have eclampsia but later diagnosed with reversible cerebral vasoconstriction syndrome (RCVS). She presented with seizures, altered mental status, nystagmus, lower extremity weakness, and absent reflexes. An extensive workup ruled out infectious and autoimmune causes, but a computed tomography angiogram (CTA) revealed severe cerebral vasoconstriction. Treatment included levetiracetam, intravenous magnesium, and nimodipine. The case highlights the challenge of differentiating RCVS from eclampsia in the postpartum period, emphasizing the importance of considering alternative diagnoses and brain CTA when RCVS is suspected, with calcium channel blockers potentially contributing to favorable neurological outcomes.
PubMed: 38681466
DOI: 10.7759/cureus.57021 -
Heliyon Apr 2024Subarachnoid hemorrhage (SAH) is a serious cerebrovascular emergency. The incidence of SAH and hazard ratio of death increase with age.
Olfactory three needle regulates the proliferation of olfactory bulb neural stem cells and ameliorates brain injury after subarachnoid hemorrhage by regulating Wnt/β-catenin signaling.
BACKGROUND
Subarachnoid hemorrhage (SAH) is a serious cerebrovascular emergency. The incidence of SAH and hazard ratio of death increase with age.
OBJECTIVE
In this study, we aimed to observe the effects and potential mechanisms of olfactory three needle (OTN) on cognitive impairment, neuronal activity, and neural stem cell differentiation in SAH rats.
METHODS
Sprague-Dawley (SD) rats were randomly divided into five groups: Sham, SAH group, SAH + Nimodipine (NMP) group, and SAH + OTN group. The rats in the SAH + OTN group received the OTN electroacupuncture treatment. For treatment with recombinant DKK1 (a Wnt/β-catenin inhibitor), mice were injected with DKK1.
RESULTS
Our results found that OTN improved cognitive impairment and hippocampal neuron damage in SAH rats. Furthermore, OTN promoted the proliferation of neural stem cells in SAH rats. Mechanistically, OTN activated Wnt/β-catenin signaling in SAH rats, as indicated by the increased expression levels of Wnt1, β-Catenin, LMNB1, and -GSK-3β. DKK1 reversed the improvement effect of OTN on cognitive impairment and neuronal damage in SAH rats. Meanwhile, DKK1 blocked the promoting effect of OTN on the proliferation of NSCs in SAH rats.
CONCLUSIONS
OTN electroacupuncture may be an effective therapeutic strategy for SAH.
PubMed: 38596082
DOI: 10.1016/j.heliyon.2024.e28551 -
Brain Communications 2024Aging and Alzheimer's disease are associated with chronic elevations in neuronal calcium influx L-type calcium channels. The hippocampus, a primary memory encoding...
Aging and Alzheimer's disease are associated with chronic elevations in neuronal calcium influx L-type calcium channels. The hippocampus, a primary memory encoding structure in the brain, is more vulnerable to calcium dysregulation in Alzheimer's disease. Recent research has suggested a link between L-type calcium channels and tau hyperphosphorylation. However, the precise mechanism of L-type calcium channel-mediated tau toxicity is not understood. In this study, we seeded a human tau pseudophosphorylated at 14 amino acid sites in rat hippocampal cornu ammonis 1 region to mimic soluble pretangle tau. Impaired spatial learning was observed in human tau pseudophosphorylated at 14 amino acid sites-infused rats as early as 1-3 months and worsened at 9-10 months post-infusion. Rats infused with wild-type human tau exhibited milder behavioural deficiency only at 9-10 months post-infusion. No tangles or plaques were observed in all time points examined in both human tau pseudophosphorylated at 14 amino acid sites and human tau-infused brains. However, human tau pseudophosphorylated at 14 amino acid sites-infused hippocampus exhibited a higher amount of tau phosphorylation at S262 and S356 than the human tau-infused rats at 3 months post-infusion, paralleling the behavioural deficiency observed in human tau pseudophosphorylated at 14 amino acid sites-infused rats. Neuroinflammation indexed by increased Iba1 in the cornu ammonis 1 was observed in human tau pseudophosphorylated at 14 amino acid sites-infused rats at 1-3 but not 9 months post-infusion. Spatial learning deficiency in human tau pseudophosphorylated at 14 amino acid sites-infused rats at 1-3 months post-infusion was paralleled by decreased neuronal excitability, impaired NMDA receptor-dependent long-term potentiation and augmented L-type calcium channel-dependent long-term potentiation at the cornu ammonis 1 synapses. L-type calcium channel expression was elevated in the soma of the cornu ammonis 1 neurons in human tau pseudophosphorylated at 14 amino acid sites-infused rats. Chronic L-type calcium channel blockade with nimodipine injections for 6 weeks normalized neuronal excitability and synaptic plasticity and rescued spatial learning deficiency in human tau pseudophosphorylated at 14 amino acid sites-infused rats. The early onset of L-type calcium channel-mediated pretangle tau pathology and rectification by nimodipine in our model have significant implications for preclinical Alzheimer's disease prevention and intervention.
PubMed: 38562310
DOI: 10.1093/braincomms/fcae096 -
Journal of Neurosurgery. Case Lessons Apr 2024Cerebral vasospasm is commonly associated with adult aneurysmal subarachnoid hemorrhage but can develop in children. The standard vasospasm treatment includes induced...
BACKGROUND
Cerebral vasospasm is commonly associated with adult aneurysmal subarachnoid hemorrhage but can develop in children. The standard vasospasm treatment includes induced hypertension, avoidance of hypovolemia, systemic use of the calcium channel blocker (CCB) nimodipine, and cerebral angiography for intraarterial therapy. Emerging treatments in adults, such as intraventricular CCB administration, have not been investigated in children. This study demonstrates the successful use of an intraventricular CCB in a pediatric patient with refractory vasospasm secondary to meningitis.
OBSERVATIONS
A 12-year-old female presented with Streptococcus pneumoniae meningitis and ventriculitis with refractory symptomatic cerebral vasospasm. She received a 5-day course of intrathecal nicardipine through an existing external ventricular drain. Her clinical status, transcranial Doppler studies, and radiography improved. Treatment was well tolerated.
LESSONS
Pediatric vasospasm is uncommon and potentially devastating. The management of vasospasm in adults occurs frequently. Principles of this management are adapted to pediatric care given the rarity of vasospasm in children. The use of intraventricular nicardipine has been reported in the care of adults with level 3 evidence. It has not been adequately reported in children with refractory vasospasm. Here, the first use of intraventricular nicardipine in treating pediatric cerebral vasospasm in the setting of meningitis is described and highlighted.
PubMed: 38560947
DOI: 10.3171/CASE23765 -
MedRxiv : the Preprint Server For... Mar 2024In Alzheimer's disease (AD), the most common cause of dementia, females have higher prevalence and faster progression, but sex-specific molecular findings in AD are...
In Alzheimer's disease (AD), the most common cause of dementia, females have higher prevalence and faster progression, but sex-specific molecular findings in AD are limited. Here, we comprehensively examined and validated 7,006 aptamers targeting 6,162 proteins in cerebral spinal fluid (CSF) from 2,077 amyloid/tau positive cases and controls to identify sex-specific proteomic signatures of AD. In discovery (N=1,766), we identified 330 male-specific and 121 female-specific proteomic alternations in CSF (FDR <0.05). These sex-specific proteins strongly predicted amyloid/tau positivity (AUC=0.98 in males; 0.99 in females), significantly higher than those with age, sex, and APOE-ε4 (AUC=0.85). The identified sex-specific proteins were well validated (r≥0.5) in the Stanford study (N=108) and Emory study (N=148). Biological follow-up of these proteins led to sex differences in cell-type specificity, pathways, interaction networks, and drug targets. Male-specific proteins, enriched in astrocytes and oligodendrocytes, were involved in postsynaptic and axon-genesis. The male network exhibited direct connections among 152 proteins and highlighted PTEN, NOTCH1, FYN, and MAPK8 as hubs. Drug target suggested melatonin (used for sleep-wake cycle regulation), nabumetone (used for pain), daunorubicin, and verteporfin for treating AD males. In contrast, female-specific proteins, enriched in neurons, were involved in phosphoserine residue binding including cytokine activities. The female network exhibits strong connections among 51 proteins and highlighted JUN and 14-3-3 proteins (YWHAG and YWHAZ) as hubs. Drug target suggested biperiden (for muscle control of Parkinson's disease), nimodipine (for cerebral vasospasm), quinostatin and ethaverine for treating AD females. Together, our findings provide mechanistic understanding of sex differences for AD risk and insights into clinically translatable interventions.
PubMed: 38559166
DOI: 10.1101/2024.03.15.24304164 -
FEBS Open Bio May 2024Drug repurposing is promising because approving a drug for a new indication requires fewer resources than approving a new drug. Signature reversion detects drug...
Drug repurposing is promising because approving a drug for a new indication requires fewer resources than approving a new drug. Signature reversion detects drug perturbations most inversely related to the disease-associated gene signature to identify drugs that may reverse that signature. We assessed the performance and biological relevance of three approaches for constructing disease-associated gene signatures (i.e., limma, DESeq2, and MultiPLIER) and prioritized the resulting drug repurposing candidates for four low-survival human cancers. Our results were enriched for candidates that had been used in clinical trials or performed well in the PRISM drug screen. Additionally, we found that pamidronate and nimodipine, drugs predicted to be efficacious against the brain tumor glioblastoma (GBM), inhibited the growth of a GBM cell line and cells isolated from a patient-derived xenograft (PDX). Our results demonstrate that by applying multiple disease-associated gene signature methods, we prioritized several drug repurposing candidates for low-survival cancers.
Topics: Drug Repositioning; Humans; Antineoplastic Agents; Animals; Cell Line, Tumor; Mice; Glioblastoma; Gene Expression Profiling; Xenograft Model Antitumor Assays; Gene Expression Regulation, Neoplastic; Brain Neoplasms; Neoplasms; Transcriptome
PubMed: 38531616
DOI: 10.1002/2211-5463.13796 -
Scientific Reports Mar 2024Intra-arterial nimodipine administration is a widely used rescue therapy for cerebral vasospasm. Although it is known that its effect sets in with delay, there is little... (Review)
Review
Intra-arterial nimodipine administration is a widely used rescue therapy for cerebral vasospasm. Although it is known that its effect sets in with delay, there is little evidence in current literature. Our aim was to prove that the maximal vasodilatory effect is underestimated in direct angiographic controls. We reviewed all cases of intra-arterial nimodipine treatment for subarachnoid hemorrhage-related cerebral vasospasm between January 2021 and December 2022. Inclusion criteria were availability of digital subtraction angiography runs before and after nimodipine administration and a delayed run for the most affected vessel at the end of the procedure to decide on further escalation of therapy. We evaluated nimodipine dose, timing of administration and vessel diameters. Delayed runs were performed in 32 cases (19 patients) with a mean delay of 37.6 (± 16.6) min after nimodipine administration and a mean total nimodipine dose of 4.7 (± 1.2) mg. Vessel dilation was more pronounced in delayed vs. immediate controls, with greater changes in spastic vessel segments (n = 31: 113.5 (± 78.5%) vs. 32.2% (± 27.9%), p < 0.0001) vs. non-spastic vessel segments (n = 32: 23.1% (± 13.5%) vs. 13.3% (± 10.7%), p < 0.0001). In conclusion intra-arterially administered nimodipine seems to exert a delayed vasodilatory effect, which should be considered before escalation of therapy.
Topics: Humans; Nimodipine; Vasodilator Agents; Vasospasm, Intracranial; Subarachnoid Hemorrhage; Angiography, Digital Subtraction
PubMed: 38486099
DOI: 10.1038/s41598-024-56807-7 -
Cureus Jan 2024Background Managing neurocritical care patients encompasses many complex challenges, necessitating specialized care and continuous quality improvement efforts. In recent...
Background Managing neurocritical care patients encompasses many complex challenges, necessitating specialized care and continuous quality improvement efforts. In recent years, the focus on enhancing patient outcomes in neurocritical care may have led to the development of dedicated quality improvement programs. These programs are designed to systematically evaluate and refine care practices, aligning them with the latest clinical guidelines and research findings. Objective To describe the structure, processes, and outcomes of a dedicated Neurocritical Care Quality Improvement Program (NCC-QIP) at Harborview Medical Center, United States; a quaternary academic medical center, level I trauma, and a comprehensive stroke center. Materials and methods We describe the development of the NCC-QIP, its structure, function, challenges, and evolution. We examine our performance with several NCC-QI quality measures as proposed by the Joint Commission, the American Association of Neurology, and the Neurocritical Care Society, self-reported quality improvement (QI) concerns and QI initiatives undertaken because of the information obtained during our event/measure reporting process for patients admitted between 1/1/2014 and 06/30/2023. Results The NCC-QI reviewed data from 20,218 patients; mean age 57.9 (standard deviation 18.1) years, 56% (n=11,326) males, with acute ischemic stroke (AIS; 22.3%, n=4506), spontaneous intracerebral hemorrhage (ICH; 14.8%, n=2,996), spontaneous subarachnoid hemorrhage (SAH; 8.9%, n=1804), and traumatic brain injury (TBI; 16.6%, n=3352) among other admissions, 37.4% (n=7,559) were mechanically ventilated, and 13.6% (n=2,753) received an intracranial pressure monitor. The median intensive care unit length of stay was two days (Quartile 1-Quartile 3: 2-5 days), and the median hospital length of stay was seven days (Quartile 1-Quartile 3: 3-14 days); 53.9% (n=10,907) were discharged home while 11.4% (2,309) died. The three most commonly reported QI concerns were related to care coordination/communication/handoff (40.4%, n=283), medication-related concerns (14.9%, n=104), and equipment/devices-related concerns (11.7%, n=82). Hospital-acquired infections were in the form of ventilator-associated pneumonia (16.3%, n=419/2562), ventriculostomy catheter-associated infections (4%, n=102/2246), and deep venous thrombosis/pulmonary embolism (3.2%, n=647). The quality metrics documentation was as follows: nimodipine after SAH (99.8%, 1802/1810), Hunt and Hess score (36%, n=650/1804), and ICH score (58.4% n=1752/2996). In comparison, 72% (n=3244/4506) of patients with AIS had a documented National Institute of Health Stroke Scale. Admission Glasgow Coma Score was recorded in 99% of patients with SAH, ICH, and TBI. Educational modules were implemented in response to event reporting. Conclusion A dedicated NCC-QIP can be successfully implemented at a quaternary medical medical center. It is possible to monitor and review a large volume of neurocritical care patients, The three most reported NCC-QI concerns may be related to care coordination-communication/handoff, medication-related concerns, and equipment/devices-related complications. The documentation of illness severity scores and stroke measures depends upon the type of measure and ability to reliably and accurately abstract and can be challenging. The quality improvement process can be enhanced by educational modules that reinforce quality and safety.
PubMed: 38384632
DOI: 10.7759/cureus.52730