The Role of Astrocytes in Migraine with Cortical Spreading Depression: Protagonists or Bystanders? A Narrative Review.

Cortical spreading depression (CSD) is a slow wave of cortical depolarization closely associated with migraines with an aura. Previously, it was thought that CSD depolarization was mainly driven by neurons, with characteristic changes in neuronal swelling and increased extracellular potassium (K+) and glutamate. However, the role of astrocytes, a member of the neurovascular unit, in migraine with CSD has recently received increasing attention. In the early stages of CSD, astrocytes provide neurons with energy support and clear K+ and glutamate from synaptic gaps. However, in the late stages of CSD, astrocytes release large amounts of lactic acid to exacerbate hypoxia when the energy demand exceeds the astrocytes' compensatory capacity. Astrocyte endfoot swelling is a characteristic of CSD, and neurons are not similarly altered. It is primarily due to K+ influx and abnormally active calcium (Ca2+) signaling. Aquaporin 4 (AQP-4) only mediates K+ influx and has little role as an aquaporin. Astrocytes endfoot swelling causes perivascular space closure, slowing the glymphatic system flow and exacerbating neuroinflammation, leading to persistent CSD. Astrocytes are double-edged swords in migraine with CSD and may be potential targets for CSD interventions.

Profile of Chinese Cluster Headache Register Individual Study (CHRIS): Clinical characteristics, diagnosis and treatment status data of 816 patients in China.

BACKGROUND: The clinical profile of cluster headache may differ among different regions of the world, warranting interest in the data obtained from the initial Chinese Cluster Headache Register Individual Study (CHRIS) for better understanding. METHODS: We conducted a multicenter, prospective, longitudinal cohort study on cluster headache across all 31 provinces of China, aiming to gather clinical characteristics, treatment approaches, imaging, electrophysiological and biological samples. RESULTS: In total 816 patients were enrolled with a male-to-female ratio of 4.33:1. The mean age at consultation was 34.98 ± 9.91 years, and 24.89 ± 9.77 years at onset. Only 2.33% were diagnosed with chronic cluster headache, and 6.99% had a family history of the condition. The most common bout was one to two times per year (45.96%), lasting two weeks to one month (44.00%), and occurring frequently in spring (76.23%) and winter (73.04%). Of these, 68.50% experienced one to two attacks per day, with the majority lasting one to two hours (45.59%). The most common time for attacks was between 9 am and 12 pm (75.86%), followed by 1 am and 3 am (43.48%). Lacrimation (78.80%) was the most predominant autonomic symptom reported. Furthermore, 39.22% of patients experienced a delay of 10 years or more in receiving a correct diagnosis. Only 35.67% and 24.26% of patients received common acute and preventive treatments, respectively. CONCLUSION: Due to differences in ethnicity, genetics and lifestyle conditions, CHRIS has provided valuable baseline data from China. By establishing a dynamic cohort with comprehensive multidimensional data, it aims to advance the management system for cluster headache in China.

Paroxysmal Sympathetic Hyperactivity After Acquired Brain Injury: An Integrative Review of Diagnostic and Management Challenges.

Paroxysmal sympathetic hyperactivity (PSH) mainly occurs after acquired brain injury (ABI) and often presents with high fever, hypertension, tachycardia, tachypnea, sweating, and dystonia (increased muscle tone or spasticity). The pathophysiological mechanisms of PSH are not fully understood. Currently, there are several views: (1) disconnection theory, (2) excitatory/inhibitory ratio, (3) neuroendocrine function, and (4) neutrophil extracellular traps. Early diagnosis of PSH remains difficult, given the low specificity of its diagnostic tools and unclear pathogenesis. According to updated case analyses in recent years, PSH is now more commonly observed in patients with stroke, with tachycardia and hypertension as the main clinical manifestations, which is not fully consistent with previous data. To date, the PSH Assessment Measure tool is optimal for the early identification of PSH and stratification of symptom severity. Clinical strategies for the management of PSH are divided into three main points: (1) reduction of stimulation, (2) reduction of sympathetic excitatory afferents, and (3) inhibition of the effects of sympathetic hyperactivity on target organs. However, use of drugs and standards have not yet been harmonized. Further investigation on the relationship between PSH severity and long-term neurological prognosis in patients with ABI is required. This review aimed to determine the diagnostic and management challenges encountered in PSH after ABI.

Rectangular method: a modified technique for sampling the ischemic border zone in a rat model of transient middle cerebral artery occlusion.

To date, there have been three common methods for sampling the cerebral ischemic border zone in a rat model of transient middle cerebral artery occlusion (tMCAO): the "two o'clock method", the "diagonal method", and the "parallel line method". However, these methods have their own advantages and limitations. Here, we propose a modified technique (the "rectangular method") for sampling the ischemic border zone. A rat tMCAO model was prepared under the support of a compact small animal anesthesia machine. Cerebral blood flow was monitored by high-resolution laser Doppler to control the quality of modeling, and 2,3,5-triphenyl tetrazolium chloride (TTC) staining was used for cerebral infarction location assessment. Superoxide dismutase 2 (SOD2), cysteinyl aspartate specific proteinase (caspase)-3, caspase-9, and heat shock protein 70 (HSP70) were used to verify the reliability and reproducibility of the rectangular method. The expression of biomarkers (SOD2, caspase-3, caspase-9, and HSP70) in the traditional (two o'clock method after TTC staining) and modified (rectangular method) groups were increased. There were no significant differences between the groups. The rectangular method proposed herein is based on a modification of the diagonal method and parallel line method, which could provide a directly observable infarct borderline and a sufficient sampling area for subsequent experimental operations regardless of the cerebral infarct location. The assessed biomarkers (SOD2, caspase-3, caspase-9, and HSP70) demonstrated the reliability and reproducibility of the rectangular method, which may facilitate inter-laboratory comparisons.

Rapamycin Responds to Alzheimer's Disease: A Potential Translational Therapy.

Alzheimer's disease (AD) is a sporadic or familial neurodegenerative disease of insidious onset with progressive cognitive decline. Although numerous studies have been conducted or are underway on AD, there are still no effective drugs to reverse the pathological features and clinical manifestations of AD. Rapamycin is a macrolide antibiotic produced by Streptomyces hygroscopicus. As a classical mechanistic target of rapamycin (mTOR) inhibitor, rapamycin has been shown to be beneficial in a variety of AD mouse and cells models, both before the onset of disease symptoms and the early stage of disease. Although many basic studies have demonstrated the therapeutic effects of rapamycin in AD, many questions and controversies remain. This may be due to the variability of experimental models, different modes of administration, dose, timing, frequency, and the availability of drug-targeting vehicles. Rapamycin may delay the development of AD by reducing ß-amyloid (Aß) deposition, inhibiting tau protein hyperphosphorylation, maintaining brain function in APOE ε4 gene carriers, clearing chronic inflammation, and improving cognitive dysfunction. It is thus expected to be one of the candidates for the treatment of Alzheimer's disease.

Case report: Hypnic headache responds to agomelatine-a potential prophylactic treatment option.

Introduction: Hypnic headache (HH) is a rare primary headache that is characterized by strict sleep-related attacks. However, the pathophysiology of HH remains unclear. The nocturnal nature of this activity suggests a hypothalamic involvement. The pathogenesis of HH may involve the brain structure that regulates circadian rhythms and is related to an imbalance between hormones, such as melatonin and serotonin. Currently, evidence-based medicine for HH pharmacotherapy is lacking. Acute and prophylactic treatment of HH is based on only a few case reports. Here, we report a case study in which agomelatine showed desirable responsiveness for the prophylactic treatment of HH for the first time. Case description: We present the case of a 58-year-old woman with a 3-year history of nocturnal left temporal pain that awakened her during the wee hours. Brain magnetic resonance imaging did not reveal any midline structural abnormalities associated with circadian rhythms. Polysomnography revealed headache-related awakening at approximately 5:40 am, after the last rapid eye movement phase. No sleep apnea-hypopnea events were observed, without oxygen saturation or blood pressure abnormalities. The patient was prescribed agomelatine 25 mg at bedtime as a prophylactic treatment. In the following month, the frequency and severity of the headaches decreased by 80%. After 3 months, the patient's headache completely resolved, and the medication was discontinued. Conclusion: HH only occurs during sleep in the real world, leading to substantial sleep disturbances in older populations. Headache center neurologists need to focus on the prophylactic treatment of patients before bedtime to avoid nocturnal awakening. Agomelatine is a potential prophylactic treatment option for patients with HH.

Heterozygous Pathogenic and Likely Pathogenic Symptomatic HTRA1 Variant Carriers in Cerebral Small Vessel Disease.

High temperature requirement serine peptidase A1 (HTRA1) related cerebral small vessel disease (CSVD) includes both symptomatic heterozygous HTRA1 variant carrier and cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) patients. Presently, most reported symptomatic heterozygous HTRA1 variant carrier cases are sporadic family reports with a lack of specific characteristics. Additionally, the molecular mechanism of heterozygous HTRA1 gene variants is unclear. We conducted this review to collect symptomatic carriers of heterozygous HTRA1 gene variants reported as of 2022, analyzed all pathogenicity according to American College of Medical Genetics and Genomics (ACMG) variant classification, and summarized the cases with pathogenic and likely pathogenic HTRA1 variants gender characteristics, age of onset, geographical distribution, initial symptoms, clinical manifestations, imaging signs, HTRA1 gene variant information and to speculate its underlying pathogenic mechanisms. In this review, we summarized the following characteristics of pathogenic and likely pathogenic symptomatic HTRA1 variant carriers: to date, the majority of reported symptomatic HTRA1 carriers are in European and Asian countries, particularly in China which was found to have the highest number of reported cases. The age of first onset is mostly concentrated in the fourth and fifth decades. The heterozygous HTRA1 gene variants were mostly missense variants. The two variant sites, 166-182 aa and 274-302 aa, were the most concentrated. Clinicians need to pay attention to de novo data and functional data, which may affect the pathogenicity analysis. The decrease in HtrA1 protease activity is currently the most important explanation for the genetic pathogenesis.

Rectangular method: a modified technique for sampling the ischemic border zone in a rat model of transient middle cerebral artery occlusion

To date, there have been three common methods for sampling the cerebral ischemic border zone in a rat model of transient middle cerebral artery occlusion (tMCAO): the "two o'clock method", the "diagonal method", and the "parallel line method". However, these methods have their own advantages and limitations. Here, we propose a modified technique (the "rectangular method") for sampling the ischemic border zone. A rat tMCAO model was prepared under the support of a compact small animal anesthesia machine. Cerebral blood flow was monitored by high-resolution laser Doppler to control the quality of modeling, and 2,3,5-triphenyl tetrazolium chloride (TTC) staining was used for cerebral infarction location assessment. Superoxide dismutase 2 (SOD2), cysteinyl aspartate specific proteinase (caspase)-3, caspase-9, and heat shock protein 70 (HSP70) were used to verify the reliability and reproducibility of the rectangular method. The expression of biomarkers (SOD2, caspase-3, caspase-9, and HSP70) in the traditional (two o'clock method after TTC staining) and modified (rectangular method) groups were increased. There were no significant differences between the groups. The rectangular method proposed herein is based on a modification of the diagonal method and parallel line method, which could provide a directly observable infarct borderline and a sufficient sampling area for subsequent experimental operations regardless of the cerebral infarct location. The assessed biomarkers (SOD2, caspase-3, caspase-9, and HSP70) demonstrated the reliability and reproducibility of the rectangular method, which may facilitate inter-laboratory comparisons.

Adie's Pupil: A Diagnostic Challenge for the Physician.

Adie's pupil, also called tonic pupil, is mainly seen in young women. Most patients have unilateral eye involvement. The pupil of the affected side is significantly larger than that on the healthy side. The direct and indirect light reflection from the pupil on the affected side disappears. The pupil on the affected side is sensitive to low concentrations of pilocarpine. The pathogeneses of Adie's pupil are complex, some of which are insidious and lack corresponding specific diseases. Through a literature review, we found that Adie's pupil is mainly associated with infectious diseases, most commonly syphilis, followed by immune diseases and paraneoplastic syndromes. The ophthalmological symptoms and pupil abnormalities can disappear after active treatment of the primary disease. Pilocarpine can be used to treat ophthalmologic symptoms, such as blurred vision, for which patients might visit an ophthalmologist or neurologist. It is essential for clinicians to improve their understanding of the disease to avoid misdiagnosis. Differential diagnosis between Adie's pupil, oculomotor nerve palsy, anticholinergic drug overdose, Argyll-Robertson pupil, and congenital mydriasis need to be identified by the physician. Here, the clinical manifestations, pathogenesis, relationship between Adie's pupil and diseases, and differential diagnosis of Adie's pupil are reviewed.

Type II Alexander disease with fragile X mental retardation 1 gene mutation.

Alexander disease (AxD) is a rare, autosomal dominant genetic disorder with an incidence of approximately 1 in 27,00.000. It is caused by a missense mutation in the GFAP gene encoding the glial fibrillary acidic protein. Fragile X-associated tremor/ataxia syndrome (FXTAS) is an X-linked dominant genetic disease, usually caused by a pre-mutation: an unmethylated expansion in the range of 50-200 CGG repeats in the fragile X mental retardation 1 (FMR1) gene. The clinical manifestations of these two diseases are complex and have some similarities. Both type II AxD and FXTAS may have ataxia as the first symptom. Here, we describe a case of type II AxD with ataxia as the first symptom accompanying a hemizygous mutation in the FMR1 gene (NM_001185081, exon13, c 0.1256C>T, p.T419M, g 0.147026507C>T). A sporadic genetic mutation led us to misdiagnose the patient with FXTAS initially. Whole-genome sequencing confirmed a heterozygous mutation in the GFAP gene (NM_002055.5, exon4, c 0.1158C>A, p.N386K, g 0.6310C>A). This report indicates that when the patient's clinical manifestation is ataxia, and imaging results suggest that the midbrain, medulla oblongata, and other subcerebellar structures are atrophied, AxD should be considered. Whole-genome sequencing is thus feasible to avoid missed diagnoses and misdiagnoses.

Contrast-induced encephalopathy with significantly elevated levels of cerebrospinal fluid protein.

Contrast-induced encephalopathy (CIE) is a rare complication of angiography. According to our knowledge, the majority of CIE reports is imaging observations and rarely includes results of cerebrospinal fluid (CSF) tests. Furthermore, among the cases reporting the data for CSF testing, most of the results were normal. Here, we report a case of CIE presenting with significantly elevated levels of CSF protein. We found that the course of improvement in brain imaging findings was not consistent with the severity of clinical manifestations. The diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) sequences were normal. Considering the lack of convenient direct indicators to observe blood-brain barrier (BBB) function, changes in the levels of CSF protein may be related to BBB permeability and recovery and may serve as a potential prognostic marker.

Basilar dolichoectasia with intermural hematoma accompanied by cerebral microbleeds and white matter hyperintensities: A case report.

RATIONALE: The clinical manifestations of basilar dolichoectasia (BD) are variable. The diagnosis is based on imaging measurements. Digital subtraction angiography displays only the dilated vascular lumen and lacks visualization of the arterial wall. High-resolution Magnetic resonance imaging (MRI) can identify intramural hematoma; therefore, it may be more suitable for the imaging evaluation of BD. However, most of the existing literature pertaining to BD lacks vascular wall assessment. PATIENT CONCERNS: A 65-year-old Chinese man perceived weakness of the left upper and lower limb, double vision, dizziness, nausea, and vomiting was admitted to the emergency department. Fifteen years prior to this admission, he began taking levamlodipine besylate inconsistently for hypertension, but the level of blood pressure control was uncertain. The patient's father had a family history of hypertension. DIAGNOSES: An emergency axial computed tomography scan of the brain showed basilar artery (BA) dilation. Computed tomography angiography further indicated a maximum BA diameter of 38.94 mm. The length was >182 mm. MRI revealed acute infarctions of the right medulla oblongata and pons. Meanwhile, the patient had evidence of cerebral small vessel disease, including cerebral microbleeds and white matter hyperintensities. Whole-exome sequencing eliminated significant genetic variations consistent with clinical phenotypes. BD and intramural hematoma were further confirmed by high-resolution MRI of the arterial wall. INTERVENTIONS: Atorvastatin was admitted according to the results of the high-resolution MRI of the arterial wall. Benidipine hydrochloride was selected as a long-term anti-hypertensive drug. OUTCOMES: The patient had no symptoms of neurological damage during 3-month follow-up. LESSONS: Current evidence shows that BD has no obvious correlation with atherosclerosis. BA dissection and uncontrolled hypertension may be important factors in the progression of BD. BD-related stroke is likely to recur, and there are no standard secondary prevention measures. BD is often accompanied by cerebral microbleeds, and bleeding risk must be assessed during secondary prevention. When the BA diameter is greater than 10 mm, anti-platelet medication should be used with caution, blood pressure should be strictly controlled, and endovascular treatment should be considered.

Migraine with Brainstem Aura Accompanied by Disorders of Consciousness.

Migraine with brainstem aura (MBA) accompanied by disorders of consciousness (DOC) is a rare subtype of migraine. The pathophysiology of MBA with DOC has not been elucidated yet. Some patients have a family history of migraine, and women are more affected than men. The aura symptoms are diverse; however, when MBA is combined with DOC, the clinical manifestations are more complicated. Coma is the most common clinical manifestation. The overall duration of the patient's DOC is short and can often return to normal within half an hour. Headache often occurs after regaining consciousness and can also occur at the same time as DOC. The most common headache is located at the occipital region. Although DOC is reversible, considering the current small number of cases, we still need to improve our understanding of the disease to avoid misdiagnosis. The MBA patient's electroencephalogram and cerebral blood flow perfusion may have transient changes and may return to normal in the interictal period or after the DOC. Although triptans have traditionally been contraindicated in MBA under drug instructions, the evidence of basilar artery constriction, as postulated in MBA, is lacking. Lasmiditan is currently the first and only 5-HT 1F receptor agonist approved by the Food and Drug Administration. The calcitonin gene-related peptide receptor antagonists and monoclonal antibody therapies may be the most promising for future consideration. Here, the pathophysiology, clinical manifestations, diagnostic tools, and treatment progress for MBA with DOC are reviewed.

Wallerian degeneration of bilateral cerebral peduncles after acute carbon monoxide poisoning.

BACKGROUND: Cases of Wallerian degeneration of bilateral cerebral peduncles after acute carbon monoxide poisoning have not yet been reported. To date, most of the delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) lesions captured in magnetic resonance imaging (MRI) has been located in the subcortical white matter and basal ganglia. Here we report two cases of DEACMP with abnormalities in the bilateral cerebral peduncles. The etiology of abnormalities, which were strictly confined to the bilateral cerebral peduncles, was Wallerian degeneration secondary to upstream nerve axonal damage, making this the first report on such bilateral cerebral peduncle abnormalities after DEACMP. CASE PRESENTATION: In this report, we present two cases of DEACMP with abnormal signals in the bilateral cerebral peduncles captured during brain MRIs. Case 1 was of a 68-year-old man who presented with paroxysmal disturbance of the consciousness, left limb weakness for 16 days, and lagging responses for 2 days. Case 2 was of a 55-year-old man who was unconscious for 6 h. In addition to the above mentioned characteristics on the brain MRIs, the electroencephalography of case 1 indicated that his forehead scans had a mixture of wide sharp, sharp, and three-phase waves. Brain diffusion tensor imaging of case 2 further proved that the bilateral cerebral anomalies represented Wallerian degeneration secondary to upstream axonal damage. After the definitive diagnosis, the patients returned to the local hospital for hyperbaric oxygen therapy. CONCLUSIONS: Wallerian degeneration of the bilateral cerebral peduncles after acute carbon monoxide poisoning has never been reported before. The abnormal signals in the bilateral cerebral peduncles captured during brain MRIs indicated Wallerian degeneration secondary to upstream axonal damage; thus, these two cases may further our understanding of DEACMP imaging.

Frequency and Pathophysiology of Post-Seizure Todd's Paralysis.

Todd's paralysis, a neurological abnormality characterized by temporary limb weakness or hemiplegia, typically occurs following a seizure, without enduring consequences. Since limb weakness or hemiplegia can also be a common symptom of an acute ischemic stroke, it is often difficult to diagnose Todd's paralysis in individuals experiencing an acute ischemic stroke if they do not have a pre-existing history of epilepsy. Given that there is a limited understanding of Todd's paralysis, this review discusses the history, prevalence, clinical manifestations, duration, etiology, and diagnosis of Todd's paralysis. A few factors that may help clinicians distinguish Todd's paralysis from other clinical indications are as follows: (1) Todd's paralysis is commonly observed after partial seizures or generalized tonic-clonic seizures. (2) The incidence of Todd's paralysis is greater if the epilepsy is associated with old age or stroke history. (3) The duration of Todd's paralysis can range from minutes to days, depending on the type of seizure or whether the patient has experienced cortical structural damage. (4) The etiology of Todd's paralysis is associated with cerebral perfusion abnormality after seizures. Further research is needed to explore factors that distinguish Todd's paralysis from other indications that may lead to limb weakness in order to improve the diagnosis of Todd's paralysis.

Ischemic stroke in the combined territories of the septum pellucidum and the cingulate gyrus: A case report and literature review.

INTRODUCTION: Cases of isolated septum pellucidum infarction have not yet been reported. To date, there are only 2 stroke reports involving septum pellucidum infarction. The etiology of septum pellucidum infarction was subcallosal artery (ScA) injury. The abnormalities were strictly confined to the septum pellucidum and the right cingulated gyrus, making this the first case to report such confined abnormalities. PATIENT CONCERNS: In this report, we present a case of ischemic stroke confined to the septum pellucidum and cingulated gyrus in a 48-year-old male patient who presented with transient ischemic attack-like paroxysmal lower left limb weakness. DIAGNOSIS: Even no obvious abnormalities were revealed by an emergency computed tomography, the infarction in the combined territories of the septum pellucidum and the cingulate gyrus was detected on magnetic resonance imaging. INTERVENTIONS: Aspirin with clopidogrel was administered for 3 weeks as a secondary preventive drug. Clopidogrel was selected as a long-term antiplatelet drug based on a thromboelastogram. OUTCOMES: The patient showed no positive signs related to the nervous system in the hospital, and there was no recurrence during the 3-month follow-up. CONCLUSIONS: Infarction in the septum pellucidum and cingulate gyrus is rare and has atypical clinical manifestations. Physical examination may not yield obvious positive signs. False-negative computed tomography findings of the head may result in misdiagnosis. Thus, it is necessary to perform whole-brain magnetic resonance imaging in time. Moreover, ScA protection should be paid attention to during surgery for anterior communicating artery aneurysm.

Upregulation of miR-107 Inhibits Glioma Angiogenesis and VEGF Expression.

MicroRNAs can function as oncogenes or tumor suppressors in glioma. Previously, we showed that miR-107 inhibits glioma cell proliferation, migration, and invasion. Since tumor growth and invasion are closely related to angiogenesis, we further examined the role of miR-107 in glioma angiogenesis. In a co-culture of glioma cells and human brain microvascular endothelial cells (HBMVEC), overexpression of miR-107 in glioma cells led to the inhibition of HBMVEC proliferation, migration, and tube formation ability. ELISA, RT-PCR, and western blot assays revealed that upregulation of miR-107 in glioma cells inhibits VEGF expression. Our findings collectively support the critical involvement of miR-107 in glioma cell angiogenesis and highlight its potential as a therapeutic target for glioma.

Dantrolene enhances the protective effect of hypothermia on cerebral cortex neurons.

Therapeutic hypothermia is the most promising non-pharmacological neuroprotective strategy against ischemic injury. However, shivering is the most common adverse reaction. Many studies have shown that dantrolene is neuroprotective in in vitro and in vivo ischemic injury models. In addition to its neuroprotective effect, dantrolene neutralizes the adverse reaction of hypothermia. Dantrolene may be an effective adjunctive therapy to enhance the neuroprotection of hypothermia in treating ischemic stroke. Cortical neurons isolated from rat fetuses were exposed to 90 minutes of oxygen-glucose deprivation followed by reoxygenation. Neurons were treated with 40 µM dantrolene, hypothermia (at 33°C), or the combination of both for 12 hours. Results revealed that the combination of dantrolene and hypothermia increased neuronal survival and the mitochondrial membrane potential, and reduced intracellular active oxygen cytoplasmic histone-associated DNA fragmentation, and apoptosis. Furthermore, improvements in cell morphology were observed. The combined treatment enhanced these responses compared with either treatment alone. These findings indicate that dantrolene may be used as an effective adjunctive therapy to enhance the neuroprotective effects of hypothermia in ischemic stroke.

Intermittent hypothermia is neuroprotective in an in vitro model of ischemic stroke.

OBJECTIVE: To investigate whether the intermittent hypothermia (IH) protects neurons against ischemic insult and the potential molecular targets using an in vitro ischemic model of oxygen glucose deprivation (OGD). METHODS: Fetal rat cortical neurons isolated from Day E18 rat embryos were subjected to 90-min OGD and hypothermia treatments during reoxygenation before examining the changes in microscopic morphology, cell viability, microtubule- associated protein 2 (MAP-2) release, intracellular pH value and calcium, reactive oxygen species (ROS) generation, mitochondrial membrane potential (△Ψm) and neuronal death using cell counting kit (CCK-8), enzyme-linked immunosorbent assay (ELISA), BCECF AM, Fluo-3 AM, DCFH-DA and dihydroethidium (DHE), JC-1 staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), respectively. RESULTS: 90-min OGD induced morphologic abnormalities, cell viability decline, MAP-2 release, intracellular acidosis, calcium overload, increased ROS generation, △Ψm decrease and cell death in primary neurons, which was partially inhibited by continuous hypothermia (CH) and intermittent hypothermia (IH). Interestingly, 6-h CH was insufficient to reduce intracellular calcium overload and stabilize mitochondrial membrane potential (△Ψm), while 12-h CH was effective in reversing the above changes. All IH treatments (6×1 h, 4×1.5 h or 3×2 h) effectively attenuated intracellular free calcium overload, inhibited ROS production, stabilized mitochondrial membrane potential (△Ψm) and reduced delayed cell death in OGD-treated cells. However, only IH intervals longer than 1.5 h appeared to be effective in preventing cell viability loss and intracellular pH decline. CONCLUSION: Both CH and IH were neuroprotective in an in vitro model of ischemic stroke, and in spite of shorter hypothermia duration, IH could provide a comparable neuroprotection to CH.

The failure of animal models of neuroprotection in acute ischemic stroke to translate to clinical efficacy.

The discrepancy in results regarding neuroprotective agents in animal experiments compared to clinical trials is a major problem. While many neuroprotective agents have been proven effective in a variety of animal ischemic stroke models, none have been shown to work in phase III clinical trials. This review retrospectively summarizes the neuroprotectants selected for human randomized controlled trials (RCT) and explores the reasons behind the clinical translational failure of these agents. Here, we suggest that there are many factors (model selection, anesthetic choice, physiological monitoring, model success criteria, embolus property, reperfusion damage, infarction area, therapeutic time window, drug penetration, blood concentration, gender difference, and outcome evaluation) responsible for this phenomenon. Ultra-early treatment using a "home run" drug and multi-target therapy may be the most promising for future consideration.