Neurobehavioral testing in subarachnoid hemorrhage: A review of methods and current findings in rodents

Turan, Nefize; Miller, Brandon A.; Heider, Robert A.; Nadeem, Maheen; Sayeed, Iqbal; Stein, Donald G.; Pradilla, Gustavo

doi:10.1177/0271678x16665623

Cited by 39 publications

(27 citation statements)

References 154 publications

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“…Sham-operated controls received the same procedure without inserting the filament. Animals were recovered for 24 hours, then all rats were assessed with the standard 5-point neuroscore scale to evaluate neurological outcomes 11 . CSF (at least 50 μL per rat) was collected from the cisterna magna for JC1 analysis.…”

Section: Methodsmentioning

confidence: 99%

Extracellular Mitochondria in Cerebrospinal Fluid and Neurological Recovery After Subarachnoid Hemorrhage

Chou

Lan

Esposito

et al. 2017

Stroke

104

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Background and Purpose Recent studies suggest that extracellular mitochondria may be involved in the pathophysiology of stroke. In this study, we assessed the functional relevance of endogenous extracellular mitochondria in cerebrospinal fluid (CSF) in rats and humans after subarachnoid hemorrhage (SAH). Methods A standard rat model of SAH was used, where an intraluminal suture was used to perforate a cerebral artery, thus leading to blood extravasation into subarachnoid space. At 24 and 72 hrs post-SAH, neurological outcomes were measured, and the standard JC1 assay was used to quantify mitochondrial membrane potentials in the CSF. To further support the rat model experiments, CSF samples were obtained from 41 SAH patients and 27 control subjects. Mitochondrial membrane potentials were measured with the JC1 assay, and correlations with clinical outcomes were assessed at 3 months. Results In the standard rat model of SAH, extracellular mitochondria was detected in CSF at 24 and 72 hrs after injury. JC1 assays demonstrated that mitochondrial membrane potentials in CSF were decreased after SAH compared with sham-operated controls. In human CSF samples, extracellular mitochondria were also detected, and JC1 levels were also reduced after SAH. Furthermore, higher mitochondrial membrane potentials in the CSF was correlated with good clinical recovery at 3 months after SAH onset. Conclusions This proof-of-concept study suggests that extracellular mitochondria may provide a “biomarker-like” glimpse into brain integrity and recovery after injury.

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Section: Methodsmentioning

confidence: 99%

Extracellular Mitochondria in Cerebrospinal Fluid and Neurological Recovery After Subarachnoid Hemorrhage

Chou

Lan

Esposito

et al. 2017

Stroke

104

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“…An alternative prognosis, using Russell and Smith’s classification, is divided as severe or very severe [ 8 ]. Considering that detailed classification helps to determine the severity of injury, informs treatment options and is used to assess prognosis and functional recovery, recent suggestions have indicated that better diagnostic and assessment criteria are needed in the TBI field [ 9 , 10 ].…”

Section: Types Of Traumatic Brain Injuries In Humansmentioning

confidence: 99%

Overview of Traumatic Brain Injury: An Immunological Context

Nizamutdinov

Shapiro

2017

Brain Sciences

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Traumatic brain injury (TBI) afflicts people of all ages and genders, and the severity of injury ranges from concussion/mild TBI to severe TBI. Across all spectrums, TBI has wide-ranging, and variable symptomology and outcomes. Treatment options are lacking for the early neuropathology associated with TBIs and for the chronic neuropathological and neurobehavioral deficits. Inflammation and neuroinflammation appear to be major mediators of TBI outcomes. These systems are being intensively studies using animal models and human translational studies, in the hopes of understanding the mechanisms of TBI, and developing therapeutic strategies to improve the outcomes of the millions of people impacted by TBIs each year. This manuscript provides an overview of the epidemiology and outcomes of TBI, and presents data obtained from animal and human studies focusing on an inflammatory and immunological context. Such a context is timely, as recent studies blur the traditional understanding of an “immune-privileged” central nervous system. In presenting the evidence for specific, adaptive immune response after TBI, it is hoped that future studies will be interpreted using a broader perspective that includes the contributions of the peripheral immune system, to central nervous system disorders, notably TBI and post-traumatic syndromes.

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“…EBI occurs in 12% of patients after SAH and is caused by a combination of transient global ischemia associated with abrupt increase in intracranial pressure plus the toxic effects of blood in the subarachnoid space. It is characterized by neuroinflammation, blood–brain barrier (BBB) disruption, cerebral edema, and neuronal cell death . DCI occurs in ~30–40% of patients after SAH, is multifactorial in etiology, and is characterized by delayed onset of ischemic neurological deficits and/or radiographic evidence of cerebral infarction.…”

Section: Introductionmentioning

confidence: 99%

Minocycline protects against delayed cerebral ischemia after subarachnoid hemorrhage via matrix metalloproteinase‐9 inhibition

Vellimana

Zhou

Singh

et al. 2017

Ann Clin Transl Neurol

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ObjectiveDelayed cerebral ischemia (DCI) is an independent risk factor for poor outcome after aneurysmal subarachnoid hemorrhage (SAH) and is multifactorial in etiology. While prior studies have suggested a role for matrix metalloproteinase‐9 (MMP‐9) in early brain injury after SAH, its contribution to the pathophysiology of DCI is unclear.MethodsIn the first experiment, wild‐type (WT) and MMP‐9−/− mice were subjected to sham or endovascular perforation SAH surgery. In separate experiments, WT and MMP‐9−/−mice were administered vehicle or minocycline either pre‐ or post‐SAH. All mice underwent assessment of multiple components of DCI including vasospasm, neurobehavioral function, and microvessel thrombosis. In another experiment, rabbits were subjected to sham or cisterna magna injection SAH surgery, and administered vehicle or minocycline followed by vasospasm assessment.Results MMP‐9 expression and activity was increased after SAH. Genetic (MMP‐9−/− mice) and pharmacological (pre‐SAH minocycline administration) inhibition of MMP‐9 resulted in decreased vasospasm and neurobehavioral deficits. A therapeutically feasible strategy of post‐SAH administration of minocycline resulted in attenuation of multiple components of DCI. Minocycline administration to MMP‐9−/− mice did not yield additional protection. Consistent with experiments in mice, both pre‐ and post‐SAH administration of minocycline attenuated SAH‐induced vasospasm in rabbits.Interpretation MMP‐9 is a key player in the pathogenesis of DCI. The consistent attenuation of multiple components of DCI with both pre‐ and post‐SAH administration of minocycline across different species and experimental models of SAH, combined with the excellent safety profile of minocycline in humans suggest that a clinical trial in SAH patients is warranted.

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Neurobehavioral testing in subarachnoid hemorrhage: A review of methods and current findings in rodents

Cited by 39 publications

References 154 publications

Extracellular Mitochondria in Cerebrospinal Fluid and Neurological Recovery After Subarachnoid Hemorrhage

Extracellular Mitochondria in Cerebrospinal Fluid and Neurological Recovery After Subarachnoid Hemorrhage

Overview of Traumatic Brain Injury: An Immunological Context

Minocycline protects against delayed cerebral ischemia after subarachnoid hemorrhage via matrix metalloproteinase‐9 inhibition

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