Effect of Anti-inflammatory Treatment with AMD3100 and CX3CR1 Deficiency on GABAA Receptor Subunit and Expression of Glutamate Decarboxylase Isoforms After Stroke

AbstractFollowing stroke, attenuation of detrimental inflammatory pathways might be a promising strategy to improve long-term outcome. In particular, cascades driven by pro-inflammatory chemokines interact with neurotransmitter systems such as the GABAergic system. This crosstalk might be of relevance for mechanisms of neuronal plasticity, however, detailed studies are lacking. The purpose of this study was to determine if treatment with 1,1′-[1,4-phenylenebis(methylene)]bis[1,4,8,11-tetraazacyclotetradecane] (AMD3100), an antagonist to the C-X-C chemokine receptor type 4 (CXCR4) and partial allosteric agonist to CXCR7 (AMD3100) alone or in combination with C-X3-C chemokine receptor type 1 (CX3CR1) deficiency, affect the expression of GABAA subunits and glutamate decarboxylase (GAD) isoforms. Heterozygous, CX3CR1-deficient mice and wild-type littermates were subjected to photothrombosis (PT). Treatment with AMD3100 (0.5 mg/kg twice daily i.p.) was administered starting from day 2 after induction of PT until day 14 after the insult. At this time point, GABAA receptor subunits (α3, β3, δ), GAD65 and GAD67, and CXCR4 were analyzed from the peri-infarct tissue and homotypic brain regions of the contralateral hemisphere by quantitative real-time PCR and Western Blot. Fourteen days after PT, CX3CR1 deficiency resulted in a significant decrease of the three GABAA receptor subunits in both the lesioned and the contralateral hemisphere compared to sham-operated mice. Treatment with AMD3100 promoted the down-regulation of GABAA subunits and GAD67 in the ipsilateral peri-infarct area, while the β3 subunit and the GAD isoforms were up-regulated in homotypic regions of the contralateral cortex. Changes in GABAA receptor subunits and GABA synthesis suggest that the CXCR4/7 and CX3CR1 signaling pathways are involved in the regulation of GABAergic neurotransmission in the post-ischemic brain.

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Critical brain regions related to post-stroke aphasia severity identified by early diffusion imaging are not the same when predicting short- and long-term outcome

Brain and Language ◽

10.1016/j.bandl.2018.08.005 ◽

2018 ◽

Vol 186 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Chiara Zavanone ◽

Yves Samson ◽

Céline Arbizu ◽

Sophie Dupont ◽

Didier Dormont ◽

...

Keyword(s):

Diffusion Imaging ◽

Brain Regions ◽

Term Outcome ◽

Long Term Outcome ◽

Post Stroke ◽

Short And Long Term

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Effects of early stress on brain structure and function: Implications for understanding the relationship between child maltreatment and depression

Development and Psychopathology ◽

10.1017/s0954579401003030 ◽

2001 ◽

Vol 13 (3) ◽

pp. 451-471 ◽

Cited By ~ 144

Author(s):

JOAN KAUFMAN ◽

DENNIS CHARNEY

Keyword(s):

Child Maltreatment ◽

Child Protection ◽

Animal Studies ◽

Developmental Stages ◽

Brain Regions ◽

Term Outcome ◽

Long Term Outcome ◽

Modifying Factors ◽

Early Stress

Child abuse is associated with markedly elevated rates of major depression (MDD) in child, adolescent, and adult cohorts. This article reviews preclinical (e.g., animal) studies of the effects of early stress and studies of the neurobiological correlates of MDD in adults and children, and it highlights differences in the neurobiological correlates of MDD and stress at various developmental stages. The preclinical studies demonstrate that stress early in life can alter the development multiple neurotransmitter systems and promote structural and functional alterations in brain regions similar to those seen in adults with depression. Preclinical and clinical studies suggest, however, that long-term neurobiological changes associated with early stress can be modified by familial/genetic factors, the quality of the subsequent caregiving environment, and pharmacological interventions. Little is known about how developmental factors interact with experiences of early stress and these other modifying factors. Moreover, in cases of child maltreatment, the effects of early abuse are often exacerbated by failures in the child protection system and repeat out-of-home placements. Given the number of factors that impact on the long-term outcome of maltreated children, multidisciplinary research efforts are recommended to address this problem—with foci that span from neurobiology to social policy.

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Insular glioma resection: assessment of patient morbidity, survival, and tumor progression

Journal of Neurosurgery ◽

10.3171/2009.6.jns0952 ◽

2010 ◽

Vol 112 (1) ◽

pp. 1-9 ◽

Cited By ~ 181

Author(s):

Nader Sanai ◽

Mei-Yin Polley ◽

Mitchel S. Berger

Keyword(s):

Tumor Progression ◽

Malignant Transformation ◽

Progression Free Survival ◽

Brain Regions ◽

Low Grade ◽

High Grade ◽

Term Outcome ◽

Long Term Outcome ◽

Complex Anatomy ◽

High Grade Gliomas

Object Insular gliomas remain surgically challenging cases due to complex anatomy, including surrounding vasculature and the relationship to functional structures. To define the morbidity profile associated with aggressive insular glioma removal as well as its impact on long-term outcome, the authors retrospectively evaluated the extent of resection (EOR) in the context of this complex anatomy and function and assessed its role in determining disease progression, malignant transformation, and, ultimately, patient survival. Methods The study population included adults who had undergone initial or repeat resection of insular gliomas of all grades. Tumor location was identified according to a proposed quadrant-style classification (Zones I–IV) of the insula. Low- and high-grade gliomas were volumetrically analyzed using FLAIR and contrast-enhanced T1-weighted MR imaging, respectively. Results One hundred fifteen procedures involving 104 patients with insular gliomas were identified. Patients presented with low-grade gliomas (LGGs) in 70 cases (60%) and high-grade gliomas (HGGs) in 45 (40%). Zone I (anterior-superior) was the most common site within the insula (40 patients [39%]), followed by Zone I+IV (anteriorsuperior + anterior-inferior; 26 patients [25%]). The median EOR was 82% (range 31–100%) for low-grade lesions and 81% (range 47–100%) for high-grade lesions. Zone I was associated with the highest median EOR (86%), and among all lesion grades, the insular quadrant anatomy was predictive of the EOR (p = 0.0313). Overall, there were 16 deaths (15%) during a median follow-up of 4.2 years. There were no surgery-related deaths, and new, permanent postoperative deficits were noted in 6 patients (6%). Among LGGs, tumor progression and malignant transformation were identified in 20 (29%) and 14 cases (20%), respectively. Among HGGs, progression was identified in 16 cases (36%). Patients with LGGs resected ≥ 90% had a 5-year overall survival (OS) rate of 100%, whereas those with lesions resected < 90% had a 5-year OS rate of 84%. Patients with HGGs resected ≥ 90% had a 2-year OS rate of 91%; when the EOR was < 90%, the 2-year OS rate was 75%. The EOR was predictive of OS both in cases of LGGs (hazard ratio [HR] 0.955, 95% CI 0.921–0.992, p = 0.017) and HGGs (HR 0.955, 95% CI 0.918–0.994, p = 0.024). Progression-free survival (PFS) was also predicted by the EOR in both LGGs (HR 0.973, 95% CI 0.948–0.998, p = 0.0414) and HGGs (HR 0.958, 95% CI 0.919–0.999, p = 0.0475). Interestingly, among patients with LGGs, malignant progression was also significantly associated with a lower EOR (HR 0.968, 95% CI 0.393–0.998, p = 0.0369). Conclusions Aggressive resection of insular gliomas of all grades can be accomplished with an acceptable morbidity profile and is predictive of improved OS and PFS. Among insular LGGs, a greater EOR is also associated with longer malignant PFS. Data in this study also suggest that insular gliomas generally follow a more indolent course than similar lesions in other brain regions.

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