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1.
Brain ; 147(2): 680-697, 2024 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-37831655

RESUMO

Migraine is a common and disabling neurological disorder. The headache and sensory amplifications of migraine are attributed to hyperexcitable sensory circuits, but a detailed understanding remains elusive. A mutation in casein kinase 1 delta (CK1δ) was identified in non-hemiplegic familial migraine with aura and advanced sleep phase syndrome. Mice carrying the CK1δT44A mutation were more susceptible to spreading depolarization (the phenomenon that underlies migraine aura), but mechanisms underlying this migraine-relevant phenotype were not known. We used a combination of whole-cell electrophysiology and multiphoton imaging, in vivo and in brain slices, to compare CK1δT44A mice (adult males) to their wild-type littermates. We found that despite comparable synaptic activity at rest, CK1δT44A neurons were more excitable upon repetitive stimulation than wild-type, with a reduction in presynaptic adaptation at excitatory but not inhibitory synapses. The mechanism of this adaptation deficit was a calcium-dependent enhancement of the size of the readily releasable pool of synaptic vesicles, and a resultant increase in glutamate release, in CK1δT44A compared to wild-type synapses. Consistent with this mechanism, CK1δT44A neurons showed an increase in the cumulative amplitude of excitatory post-synaptic currents, and a higher excitation-to-inhibition ratio during sustained activity compared to wild-type. At a local circuit level, action potential bursts elicited in CK1δT44A neurons triggered an increase in recurrent excitation compared to wild-type, and at a network level, CK1δT44A mice showed a longer duration of 'up state' activity, which is dependent on recurrent excitation. Finally, we demonstrated that the spreading depolarization susceptibility of CK1δT44A mice could be returned to wild-type levels with the same intervention (reduced extracellular calcium) that normalized presynaptic adaptation. Taken together, these findings show a stimulus-dependent presynaptic gain of function at glutamatergic synapses in a genetic model of migraine, that accounts for the increased spreading depolarization susceptibility and may also explain the sensory amplifications that are associated with the disease.


Assuntos
Depressão Alastrante da Atividade Elétrica Cortical , Epilepsia , Transtornos de Enxaqueca , Enxaqueca com Aura , Camundongos , Animais , Enxaqueca com Aura/genética , Camundongos Transgênicos , Canais de Cálcio Tipo N/genética , Cálcio/metabolismo , Transtornos de Enxaqueca/genética , Mutação/genética , Depressão Alastrante da Atividade Elétrica Cortical/fisiologia
3.
Lancet Neurol ; 22(10): 934-945, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37717587

RESUMO

Migraine is an evolving, and sometimes lifelong disorder. The prevalence of episodic migraine peaks among individuals aged in their late 30s, implying a tendency for the disorder to remit with increasing age thereafter, whereas chronic migraine is more likely to persist into later life. Diagnosis and treatment of migraine in older adults, defined as individuals aged 60 years or older, is rendered more complex by increasing probabilities of atypical clinical features and comorbidities, with patients' comorbidities sometimes limiting their therapeutic options. However, the changing clinical presentation of migraine over an individual's lifespan is not well characterised. The neurobiological basis of remission in older adults remains unclear, although vascular, neuronal, and hormonal changes are likely to be involved. Long-term longitudinal studies of individuals with migraine would be particularly informative, with the potential not only to suggest new research directions, but also to lead to the identification of novel therapeutic agents. Although several novel migraine medications are becoming available, their effectiveness, tolerability, and safety often remain uncertain in older adults, who have commonly been excluded from the evaluation of these agents in randomised controlled trials, or who constitute only a small proportion of study populations. There is a need to recognise these limitations in the available evidence, and the specific, and often unmet, clinical needs of older adults with migraine, not least because older adults constitute an increasing proportion of populations worldwide.


Assuntos
Transtornos de Enxaqueca , Humanos , Idoso , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/epidemiologia , Neurobiologia , Probabilidade , Ensaios Clínicos Controlados Aleatórios como Assunto
4.
Headache ; 63(8): 1061-1069, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37638410

RESUMO

OBJECTIVE: To examine whether sensory hypersensitivity contributes to headache-related disability in a secondary analysis of patients with post-traumatic headache. BACKGROUND: Up to one-third of individuals with traumatic brain injuries report persistent headache 3 months post-injury. High rates of allodynia and photophobia have been observed in clinical studies and animal models of post-traumatic headache, but we do not fully understand how sensory amplifications impact post-traumatic headache-related disability. METHODS: We identified a cross-sectional sample of patients from the American Registry for Migraine Research database with new or worsening headaches post-head injury from 2016 to 2020 and performed a secondary analysis of those data. We modeled the relationship between sensory sensitivity and Migraine Disability Assessment scores using questionnaires. Candidate variables included data collection features (study site and year), headache-related and general clinical features (headache frequency, migraine diagnosis, abuse history, sex, age, cognitive and affective symptom scores), and sensory symptoms (related to light, sound, and touch sensitivity). RESULTS: The final sample included 193 patients (median age 46, IQR 22; 161/193, 83.4% female). Migraine Disability Assessment scores ranged from 0 to 260 (median 47, IQR 87). The final model included allodynia, hyperacusis, photosensitivity, headache days per month, abuse history, anxiety and depression, cognitive dysfunction, and age (R2 = 0.43). An increase of one point in allodynia score corresponded to a 3% increase in headache disability (95% CI: 0%-7%; p = 0.027), an increase of one-tenth of a point in the photosensitivity score corresponded to a 12% increase (95% CI: 3%-25%; p = 0.002), and an increase of one point in the hyperacusis score corresponded to a 2% increase (95% CI: 0%-4%; p = 0.016). CONCLUSIONS: Increased photosensitivity, allodynia, and hyperacusis were associated with increased headache-related disability in this sample of patients with post-traumatic headache. Symptoms of sensory amplification likely contribute to post-traumatic headache-related disability and merit an ongoing investigation into their potential as disease markers and treatment targets.


Assuntos
Hipersensibilidade , Transtornos de Enxaqueca , Cefaleia Pós-Traumática , Feminino , Animais , Masculino , Estudos Transversais , Hiperacusia/epidemiologia , Hiperacusia/etiologia , Hiperalgesia , Cefaleia , Transtornos de Enxaqueca/complicações , Transtornos de Enxaqueca/epidemiologia
5.
J Neurochem ; 2023 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-37596720

RESUMO

Spreading depolarization (SD) has emerged as an important contributor to the enlargement of acute brain injuries. We previously showed that the N-methyl-D-aspartate receptor antagonist ketamine was able to prevent deleterious consequences of SD in brain slices, under conditions of metabolic compromise. The current study aimed to extend these observations into an in vivo stroke model, to test whether gradients of metabolic capacity lead to differential accumulation of calcium (Ca2+ ) following SD. In addition, we tested whether ketamine protects vulnerable tissuewhile allowing SD to propagate through surrounding undamaged tissue. Focal lesions were generated using a distal middle cerebral artery occlusion in mice, and clusters of SD were generated at 20 min intervals with remote microinjection of potassium chloride. SDs invading peri-infarct regions had significantly different consequences, depending on the distance from the infarct core. Proximal to the lesion, Ca2+ transients were extended, as compared with responses in better-perfused tissue more remote from the lesion. Extracellular potential shifts were also longer and hyperemia responses were reduced in proximal regions following SDs. Consistent with in vitro studies, ketamine, at concentrations that did not abolish the propagation of SD, reduced the accumulation of intracellular Ca2+ in proximal regions following an SD wave. These findings suggest that deleterious consequences of SD can be targeted in vivo, without requiring outright block of SD initiation and propagation.

6.
J Headache Pain ; 24(1): 105, 2023 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-37553625

RESUMO

BACKGROUND: There is increasing evidence from human and animal studies that cortical spreading depression (CSD) is the neurophysiological correlate of migraine aura and a trigger of migraine pain mechanisms. The mechanisms of initiation of CSD in the brain of migraineurs remain unknown, and the mechanisms of initiation of experimentally induced CSD in normally metabolizing brain tissue remain incompletely understood and controversial. Here, we investigated the mechanisms of CSD initiation by focal application of KCl in mouse cerebral cortex slices. METHODS: High KCl puffs of increasing duration up to the threshold duration eliciting a CSD were applied on layer 2/3 whilst the membrane potential of a pyramidal neuron located very close to the site of KCl application and the intrinsic optic signal were simultaneously recorded. This was done before and after the application of a specific blocker of either NMDA or AMPA glutamate receptors (NMDARs, AMPARs) or voltage-gated Ca2+ (CaV) channels. If the drug blocked CSD, stimuli up to 12-15 times the threshold were applied. RESULTS: Blocking either NMDARs with MK-801 or CaV channels with Ni2+ completely inhibited CSD initiation by both CSD threshold and largely suprathreshold KCl stimuli. Inhibiting AMPARs with NBQX was without effect on the CSD threshold and velocity. Analysis of the CSD subthreshold and threshold neuronal depolarizations in control conditions and in the presence of MK-801 or Ni2+ revealed that the mechanism underlying ignition of CSD by a threshold stimulus (and not by a just subthreshold stimulus) is the CaV-dependent activation of a threshold level of NMDARs (and/or of channels whose opening depends on the latter). The delay of several seconds with which this occurs underlies the delay of CSD initiation relative to the rapid neuronal depolarization produced by KCl. CONCLUSIONS: Both NMDARs and CaV channels are necessary for CSD initiation, which is not determined by the extracellular K+ or neuronal depolarization levels per se, but requires the CaV-dependent activation of a threshold level of NMDARs. This occurs with a delay of several seconds relative to the rapid depolarization produced by the KCl stimulus. Our data give insights into potential mechanisms of CSD initiation in migraine.


Assuntos
Depressão Alastrante da Atividade Elétrica Cortical , Transtornos de Enxaqueca , Enxaqueca com Aura , Camundongos , Animais , Humanos , Depressão Alastrante da Atividade Elétrica Cortical/fisiologia , Maleato de Dizocilpina/farmacologia , Receptores de N-Metil-D-Aspartato
7.
Headache ; 63(5): 672-682, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37140215

RESUMO

OBJECTIVE: To present an updated version of the Utah Photophobia Symptom Impact Scale version 2 (UPSIS2), providing robust clinical and psychometric validation, to improve headache-specific evaluation of light sensitivity and headache-related photophobia. BACKGROUND: The original UPSIS filled a gap in available tools for assessment of headache-associated light sensitivity by providing patient-reported evaluation of the impact of light sensitivity on activities of daily living (ADLs). We have since revised the original questionnaire to provide a more robust item construct and refined validation approach. METHODS: We conducted a psychometric validation of the UPSIS2 through a primary analysis of an online survey of volunteers with recurrent headaches recruited from the University of Utah clinics and surrounding community. Volunteers completed the original UPSIS and UPSIS2 questionnaire versions in addition to measures of headache impact, disability, and frequency. The UPSIS2 now includes a pre-defined recall period and a 1-4 Likert scale with standardized response anchors to improve clarity. Internal construct validity, external construct validity, and test-retest reliability, were evaluated. RESULTS: Responses were obtained from 163 volunteers, with UPSIS2 scores ranging from 15 to 57 (out of a possible 15-60) with a mean (standard deviation) of 32.4 (8.80). Construct validity was satisfactory, as evidenced by sufficient unidimensionality, monotonicity, and local independence. Reliability was excellent, with Rasch test reliability = 0.90 and Cronbach's alpha = 0.92, and an intraclass correlation of 0.79 (95% confidence interval 0.65-0.88) for participants who took the test twice. UPSIS2 correlates well with other headache measures (Spearman's correlations >0.50), as well as the original UPSIS (Spearman's correlation = 0.87), indicating good convergent validity. UPSIS2 scores differ significantly across International Classification of Headache Disorders (third edition) groups, indicating good known group validity. CONCLUSION: The UPSIS2 provides a well-validated headache-specific outcome measure for the assessment of photophobia impact on ADLs.


Assuntos
Atividades Cotidianas , Fotofobia , Humanos , Fotofobia/diagnóstico , Fotofobia/etiologia , Reprodutibilidade dos Testes , Utah , Psicometria , Cefaleia , Inquéritos e Questionários
8.
J Foot Ankle Surg ; 62(4): 719-722, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37012168

RESUMO

Insertional Achilles tendonitis is a common pathology treated by foot and ankle surgeons that may require surgical intervention. Literature has shown good outcomes following detachment and reattachment of the Achilles for removal of the exostosis. However, there is minimal literature showing the impact of adding a gastrocnemius recession to the Haglund's resection. The goal of the present study was to retrospectively review the outcomes of an isolated Haglund's resection versus a Haglund's resection combined with a gastrocnemius recession. A retrospective chart review of 54 operative extremities was performed: 29 with isolated Haglund's resection and 25 with a Strayer gastrocnemius recession. We found similar decreases in pain between the 2 groups, 6.1 to 1.5 and 6.8 to 1.8 in the isolated Haglund's and Strayer's group, respectively. We found decreased postoperative Achilles rupture and reoperation rates in the Strayer group but this did not reach statistical significance. We found a statistically significant decreased rate of wound healing complications in the Strayer group, 4% in the Strayer group and 24% in the isolated procedure. In conclusion, adding a Strayer to a Haglund's resection was found to have a statistically significant decrease in wound complications. We recommend future randomized controlled studies to compare the use of a Strayer procedure on postoperative complications.


Assuntos
Tendão do Calcâneo , Bursite , Calcâneo , Exostose , Esporão do Calcâneo , Humanos , Estudos Retrospectivos , Calcâneo/cirurgia , Calcâneo/patologia , Tendão do Calcâneo/cirurgia , Extremidade Inferior , Bursite/cirurgia
9.
Wounds ; 35(4): 80-84, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-37023476

RESUMO

INTRODUCTION: Plantar hallux wounds are common in patients with diabetic neuropathy. Several techniques, both surgical and nonsurgical, are designed to offload plantar wounds. However, controversy exists regarding which techniques are superior in terms of efficacy, safety, and longevity. OBJECTIVE: This manuscript presents a simple, minimally invasive technique to permanently offload the plantar IPJ of the hallux in the case of recalcitrant plantar ulcerations. The authors describe their surgical technique for and outcomes of medially based hallux IPJ arthroplasty for the management of recalcitrant hallux ulcerations. MATERIALS AND METHODS: Five patients (6 wound cases) were evaluated. All patients underwent the same surgical procedure and were subject to the same postoperative protocol of full weight-bearing as tolerated. RESULTS: All 5 cases healed, with an average time to healing of 15.5 days (range, 10-22 days) and no instances of recurrence. The average time to final follow-up was 83.17 weeks (range, 54-95 weeks). CONCLUSIONS: The medially based hallux IPJ arthroplasty approach has demonstrated ability to adequately offload hallux ulcerations, permits bone biopsy or resection for treatment of underlying bone infection, and allows for immediate weight-bearing.


Assuntos
Neuropatias Diabéticas , Úlcera do Pé , Hallux , Humanos , Hallux/cirurgia , Úlcera do Pé/cirurgia , Artroplastia/métodos , Cicatrização , Seguimentos , Resultado do Tratamento
10.
J Foot Ankle Surg ; 62(3): 536-542, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36792480

RESUMO

Arthrodesis of the great toe joint is a valuable procedure for hallux valgus deformities. The primary aim of this study was to determine nonunion rates of a first metatarsophalangeal joint (MTPJ) arthrodesis for bunion deformity. This was a retrospective review of 166 consecutive limbs that underwent a first metatarsal phalangeal joint arthrodesis at Wake Forest Baptist Medical Center (WFBMC). Procedures were performed using 4 different constructs for the arthrodesis. Incidence of nonunion, intermetatarsal correction, infection, and recurrence were measured. Overall, 20 patients (12%) experienced nonunion following a first metatarsophalangeal joint arthrodesis. Eighty-seven patients (86%) of plate and screw patients achieved union while 14 (78%) of crossing screw patients achieved union. The minimum time of follow-up was 3 months and the maximum time was 15.4 months. The mean change in intermetatarsal and hallux valgus angle correction was 3.4° and 20.3°, with no statistical difference based on hardware construct or being diabetic. First metatarsophalangeal joint arthrodesis is a viable option for hallux valgus. However, the results of the present study suggest that there is a lower fusion rate of the first MTPJ using crossing screws for bunion deformities.


Assuntos
Joanete , Hallux Rigidus , Hallux Valgus , Hallux , Articulação Metatarsofalângica , Humanos , Hallux Valgus/diagnóstico por imagem , Hallux Valgus/cirurgia , Hallux/diagnóstico por imagem , Hallux/cirurgia , Estudos Retrospectivos , Incidência , Hallux Rigidus/cirurgia , Radiografia , Artrodese/efeitos adversos , Artrodese/métodos , Articulação Metatarsofalângica/diagnóstico por imagem , Articulação Metatarsofalângica/cirurgia , Resultado do Tratamento
11.
J Headache Pain ; 24(1): 3, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36627561

RESUMO

BACKGROUND: Despite the pervasiveness of migraine, the underlying pathophysiological mechanisms initiating migraine attacks are far from well understood and are matter of scientific debate. OBJECTIVE: In this narrative review, we discuss key evidence for that suggest a peripheral origin or central origin and provide directions for future studies that may provide further clarification. DISCUSSION: Migraine pathogenesis is considered to involve the trigeminovascular system, a term that encompasses the trigeminal nerve and its axonal projections to the intracranial blood vessels. Beyond any doubt both peripheral and central mechanisms are involved in migraine pathogenesis, but an unresolved question is the how the initial activation occurs in a migraine attack. Evidence favoring a peripheral origin of migraine attacks, i.e., initial events occur outside of the blood-brain barrier, include the importance of sensitization of perivascular sensory afferents early on in a migraine attack. Evidence favoring a central origin include the occurrence of prodromal symptoms, migraine aura, and activation of structures within the central nervous system early in and during a migraine attack. CONCLUSIONS: Both peripheral and central mechanisms are likely involved in a migraine attack, e.g., peripheral nociceptive input is necessary for pain transmission and cortical activity is necessary for pain perception. Yet, the debate of whether migraine attacks are initiated a peripheral or central site remains unresolved. The increased focus on prodromal symptoms and on the development of a human model of migraine aura will possibly provide key arguments needed to answer this question in the near future. Until then, we cannot draw firm conclusions and the debate goes on. VIDEO LINK: Video recording of the debate held at the 1st International Conference on Advances in Migraine Sciences (ICAMS 2022, Copenhagen, Denmark) is available at: https://www.youtube.com/watch?v=NC0nlcKohz0 .


Assuntos
Epilepsia , Transtornos de Enxaqueca , Enxaqueca com Aura , Humanos , Sintomas Prodrômicos , Nervo Trigêmeo , Epilepsia/complicações
12.
Transl Stroke Res ; 14(2): 160-173, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-35364802

RESUMO

Touch and other types of patient stimulation are necessary in critical care and generally presumed to be beneficial. Recent pre-clinical studies as well as randomized trials assessing early mobilization have challenged the safety of such routine practices in patients with acute neurological injury such as stroke. We sought to determine whether patient stimulation could result in spreading depolarization (SD), a dramatic pathophysiological event that likely contributes to metabolic stress and ischemic expansion in such patients. Patients undergoing surgical intervention for severe acute neurological injuries (stroke, aneurysm rupture, or trauma) were prospectively consented and enrolled in an observational study monitoring SD with implanted subdural electrodes. Subjects also underwent simultaneous video recordings (from continuous EEG monitoring) to assess for physical touch and other forms of patient stimulation (such as suctioning and positioning). The association of patient stimulation with subsequent SD was assessed. Increased frequency of patient stimulation was associated with increased risk of SD (OR = 4.39 [95%CI = 1.71-11.24]). The overall risk of SD was also increased in the 60 min following patient stimulation compared to times with no stimulation (OR = 1.19 [95%CI = 1.13-1.26]), though not all subjects demonstrated this effect individually. Positioning of the subject was the subtype of stimulation with the strongest overall effect on SD (OR = 4.92 [95%CI = 3.74-6.47]). We conclude that in patients with some acute neurological injuries, touch and other patient stimulation can induce SD (PS-SD), potentially increasing the risk of metabolic and ischemic stress. PS-SD may represent an underlying mechanism for observed increased risk of early mobilization in such patients.


Assuntos
Depressão Alastrante da Atividade Elétrica Cortical , Acidente Vascular Cerebral , Humanos , Tato , Depressão Alastrante da Atividade Elétrica Cortical/fisiologia , Acidente Vascular Cerebral/terapia
14.
Proc Natl Acad Sci U S A ; 119(48): e2119824119, 2022 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-36409897

RESUMO

Fatty acids are vital for the survival of eukaryotes, but when present in excess can have deleterious consequences. The AMP-activated protein kinase (AMPK) is an important regulator of multiple branches of metabolism. Studies in purified enzyme preparations and cultured cells have shown that AMPK is allosterically activated by small molecules as well as fatty acyl-CoAs through a mechanism involving Ser108 within the regulatory AMPK ß1 isoform. However, the in vivo physiological significance of this residue has not been evaluated. In the current study, we generated mice with a targeted germline knock-in (KI) mutation of AMPKß1 Ser108 to Ala (S108A-KI), which renders the site phospho-deficient. S108A-KI mice had reduced AMPK activity (50 to 75%) in the liver but not in the skeletal muscle. On a chow diet, S108A-KI mice had impairments in exogenous lipid-induced fatty acid oxidation. Studies in mice fed a high-fat diet found that S108A-KI mice had a tendency for greater glucose intolerance and elevated liver triglycerides. Consistent with increased liver triglycerides, livers of S108A-KI mice had reductions in mitochondrial content and respiration that were accompanied by enlarged mitochondria, suggestive of impairments in mitophagy. Subsequent studies in primary hepatocytes found that S108A-KI mice had reductions in palmitate- stimulated Cpt1a and Ppargc1a mRNA, ULK1 phosphorylation and autophagic/mitophagic flux. These data demonstrate an important physiological role of AMPKß1 Ser108 phosphorylation in promoting fatty acid oxidation, mitochondrial biogenesis and autophagy under conditions of high lipid availability. As both ketogenic diets and intermittent fasting increase circulating free fatty acid levels, AMPK activity, mitochondrial biogenesis, and mitophagy, these data suggest a potential unifying mechanism which may be important in mediating these effects.


Assuntos
Proteínas Quinases Ativadas por AMP , Ácidos Graxos , Camundongos , Animais , Fosforilação , Ácidos Graxos/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Mitocôndrias/metabolismo , Homeostase , Autofagia , Triglicerídeos/metabolismo
15.
Cell Metab ; 34(6): 919-936.e8, 2022 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-35675800

RESUMO

Elevated liver de novo lipogenesis contributes to non-alcoholic steatohepatitis (NASH) and can be inhibited by targeting acetyl-CoA carboxylase (ACC). However, hypertriglyceridemia limits the use of pharmacological ACC inhibitors as a monotherapy. ATP-citrate lyase (ACLY) generates acetyl-CoA and oxaloacetate from citrate, but whether inhibition is effective for treating NASH is unknown. Here, we characterize a new mouse model that replicates many of the pathological and molecular drivers of NASH and find that genetically inhibiting ACLY in hepatocytes reduces liver malonyl-CoA, oxaloacetate, steatosis, and ballooning as well as blood glucose, triglycerides, and cholesterol. Pharmacological inhibition of ACLY mirrors genetic inhibition but has additional positive effects on hepatic stellate cells, liver inflammation, and fibrosis. Mendelian randomization of human variants that mimic reductions in ACLY also associate with lower circulating triglycerides and biomarkers of NASH. These data indicate that inhibiting liver ACLY may be an effective approach for treatment of NASH and dyslipidemia.


Assuntos
ATP Citrato (pro-S)-Liase , Dislipidemias , Hepatopatia Gordurosa não Alcoólica , ATP Citrato (pro-S)-Liase/antagonistas & inibidores , Acetil-CoA Carboxilase , Animais , Dislipidemias/tratamento farmacológico , Dislipidemias/patologia , Fígado , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Camundongos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/patologia , Oxaloacetatos/metabolismo , Triglicerídeos
16.
Neurocrit Care ; 37(Suppl 1): 83-101, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35257321

RESUMO

BACKGROUND: When a patient arrives in the emergency department following a stroke, a traumatic brain injury, or sudden cardiac arrest, there is no therapeutic drug available to help protect their jeopardized neurons. One crucial reason is that we have not identified the molecular mechanisms leading to electrical failure, neuronal swelling, and blood vessel constriction in newly injured gray matter. All three result from a process termed spreading depolarization (SD). Because we only partially understand SD, we lack molecular targets and biomarkers to help neurons survive after losing their blood flow and then undergoing recurrent SD. METHODS: In this review, we introduce SD as a single or recurring event, generated in gray matter following lost blood flow, which compromises the Na+/K+ pump. Electrical recovery from each SD event requires so much energy that neurons often die over minutes and hours following initial injury, independent of extracellular glutamate. RESULTS: We discuss how SD has been investigated with various pitfalls in numerous experimental preparations, how overtaxing the Na+/K+ ATPase elicits SD. Elevated K+ or glutamate are unlikely natural activators of SD. We then turn to the properties of SD itself, focusing on its initiation and propagation as well as on computer modeling. CONCLUSIONS: Finally, we summarize points of consensus and contention among the authors as well as where SD research may be heading. In an accompanying review, we critique the role of the glutamate excitotoxicity theory, how it has shaped SD research, and its questionable importance to the study of early brain injury as compared with SD theory.


Assuntos
Lesões Encefálicas , Depressão Alastrante da Atividade Elétrica Cortical , Acidente Vascular Cerebral , Lesões Encefálicas/terapia , Consenso , Depressão Alastrante da Atividade Elétrica Cortical/fisiologia , Ácido Glutâmico , Humanos
17.
Neurocrit Care ; 37(Suppl 1): 11-30, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35194729

RESUMO

BACKGROUND: Within 2 min of severe ischemia, spreading depolarization (SD) propagates like a wave through compromised gray matter of the higher brain. More SDs arise over hours in adjacent tissue, expanding the neuronal damage. This period represents a therapeutic window to inhibit SD and so reduce impending tissue injury. Yet most neuroscientists assume that the course of early brain injury can be explained by glutamate excitotoxicity, the concept that immediate glutamate release promotes early and downstream brain injury. There are many problems with glutamate release being the unseen culprit, the most practical being that the concept has yielded zero therapeutics over the past 30 years. But the basic science is also flawed, arising from dubious foundational observations beginning in the 1950s METHODS: Literature pertaining to excitotoxicity and to SD over the past 60 years is critiqued. RESULTS: Excitotoxicity theory centers on the immediate and excessive release of glutamate with resulting neuronal hyperexcitation. This instigates poststroke cascades with subsequent secondary neuronal injury. By contrast, SD theory argues that although SD evokes some brief glutamate release, acute neuronal damage and the subsequent cascade of injury to neurons are elicited by the metabolic stress of SD, not by excessive glutamate release. The challenge we present here is to find new clinical targets based on more informed basic science. This is motivated by the continuing failure by neuroscientists and by industry to develop drugs that can reduce brain injury following ischemic stroke, traumatic brain injury, or sudden cardiac arrest. One important step is to recognize that SD plays a central role in promoting early neuronal damage. We argue that uncovering the molecular biology of SD initiation and propagation is essential because ischemic neurons are usually not acutely injured unless SD propagates through them. The role of glutamate excitotoxicity theory and how it has shaped SD research is then addressed, followed by a critique of its fading relevance to the study of brain injury. CONCLUSIONS: Spreading depolarizations better account for the acute neuronal injury arising from brain ischemia than does the early and excessive release of glutamate.


Assuntos
Lesões Encefálicas , Isquemia Encefálica , Depressão Alastrante da Atividade Elétrica Cortical , Encéfalo , Isquemia Encefálica/tratamento farmacológico , Depressão Alastrante da Atividade Elétrica Cortical/fisiologia , Ácido Glutâmico , Humanos , Isquemia
18.
J Neurosci ; 42(11): 2371-2383, 2022 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-34857650

RESUMO

Spreading depolarizations (SDs) of gray matter occur in the brain in different pathologic conditions, and cause varying degrees of tissue damage depending on the extent of metabolic burden on the tissue. As might be expected for such large depolarizations, neurons exhibit bursts of action potentials (APs) as the wave propagates. However, the specific role of APs in SD propagation is unclear. This is potentially consequential, since sodium channel modulation has not been considered as a therapeutic target for SD-associated disorders, because of ambiguous experimental evidence. Using whole-cell electrophysiology and single-photon imaging in acute cortical slices from male C57Bl6 mice, we tested the effects of AP blockade on SDs generated by two widely used induction paradigms. We found that AP blockade using tetrodotoxin (TTX) restricted propagation of focally induced SDs, and significantly reduced the amplitude of neuronal depolarization, as well as its Ca2+ load. TTX also abolished the suppression of spontaneous synaptic activity that is a hallmark of focally induced SD. In contrast, TTX did not affect the propagation of SD induced by global superfusion of high [K+]e containing artificial CSF (ACSF). Thus, we show that voltage-gated sodium channel (Nav)-mediated neuronal AP bursts are critical for the propagation and downstream effects of focally induced SD but are less important when the ionic balance of the extracellular space is already compromised. In doing so we corroborate the notion that two different SD induction paradigms, each relevant to different clinical situations, vary significantly in their characteristics and potentially their response to treatment.SIGNIFICANCE STATEMENT Our findings suggest that voltage-gated sodium channel (Nav) channels have a critical role in the propagation and downstream neural effects of focally induced spreading depolarization (SD). As SDs are likely induced focally in many disease conditions, these studies support sodium channel modulation, a previously underappreciated therapeutic option in SD-associated disorders, as a viable approach.


Assuntos
Canais de Sódio Disparados por Voltagem , Potenciais de Ação/fisiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Tetrodotoxina/farmacologia , Canais de Sódio Disparados por Voltagem/metabolismo
19.
Neurocrit Care ; 35(Suppl 2): 135-145, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34657268

RESUMO

BACKGROUND: Spreading depolarization (SD) has been identified as a key mediator of secondary lesion progression after acute brain injuries, and clinical studies are beginning to pharmacologically target SDs. Although initial work has focused on the N-Methyl-D-aspartate receptor antagonist ketamine, there is also interest in alternatives that may be better tolerated. We recently showed that ketamine can inhibit mechanisms linked to deleterious consequences of SD in brain slices. The present study tested the hypothesis that memantine improves recovery of brain slices after SD and explored the effects of memantine in a clinical case targeting SD. METHODS: For mechanistic studies, electrophysiological and optical recordings were made from hippocampal area CA1 in acutely prepared brain slices from mice. SDs were initiated by localized microinjection of K+ in conditions of either normal or reduced metabolic substrate availability. Memantine effects were assessed from intrinsic optical signals and extracellular potential recordings. For the clinical report, a subdural strip electrode was used for continuous electrocorticographic recording after the surgical evacuation of a chronic subdural hematoma. RESULTS: In brain slice studies, memantine (10-300 µM) did not prevent the initiation of SD, but impaired SD propagation rate and recovery from SD. Memantine reduced direct current (DC) shift duration and improved recovery of synaptic potentials after SD. In brain slices with reduced metabolic substrate availability, memantine reduced the evidence of structural disruption after the passage of SD. In our clinical case, memantine did not noticeably immediately suppress SD; however, it was associated with a significant reduction of SD duration and a reduction in the electrocorticographic (ECoG) suppression that occurs after SD. SD was completely suppressed, with improvement in neurological examination with the addition of a brief course of ketamine. CONCLUSIONS: These data extend recent work showing that N-Methyl-D-aspartate receptor antagonists can improve recovery from SD. These results suggest that memantine could be considered for future clinical trials targeting SD, and in some cases as an adjunct or alternative to ketamine.


Assuntos
Ketamina , Memantina , Animais , Encéfalo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ketamina/farmacologia , Memantina/farmacologia , Camundongos , Receptores de N-Metil-D-Aspartato
20.
Pharm Pract (Granada) ; 19(3): 2377, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34621449

RESUMO

BACKGROUND: Recent approvals for novel agents such as the small molecule Janus kinase inhibitors (JAKi), combined with the advent of biosimilars has widened the gamut of available therapeutic options in the treatment of rheumatoid arthritis (RA). This combined with the introduction of mandatory non- medical switches to biosimilars in some jurisdictions by both public and private payors has led to a significant increase in the volume of therapeutic changes for patients. Pharmacists are well positioned to ensure effective and safe transitions, however there is a significant unmet need for objective and subjective clinical guidance around therapy as well disease state monitoring in RA that facilitates best practices throughout the patient journey. OBJECTIVE: In this paper we aim to create a consensus derived monitoring algorithm for pharmacists to facilitate best practices throughout therapeutic transitions from originator biologic to other originator biologics, biosimilars, and Janus kinase inhibitors in RA. METHODS: The Nominal Group Technique (NGT) was used to understand if consensus could be found among the participants. Clinically relevant questions were developed to capture solutions to the identified unmet need. The faculty considered the questions as individuals, and privately generated answers/ideas. After discussion and consideration, the participants ranked the ideas and established a consensus. RESULTS: Based on the outcome of the consensus discussions, an algorithm was created to help guide pharmacists through therapeutic transitions in RA. The tool covers important topics such as pre-transition considerations, avoiding the nocebo effect for biosimilars, specific considerations for each drug or class, monitoring efficacy, and when to refer. CONCLUSIONS: New classes of anti-rheumatic drugs including JAKi, along with the introduction of biosimilars are presenting more opportunity for therapeutic changes and monitoring in patients with RA. We hope our evidence-based consensus derived guidance tool will assist frontline pharmacists in supporting their patients to a successful therapeutic transition in RA.

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