Neurobiology of disease
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Neurobiology of disease · Jun 2013
Mitochondrial JNK phosphorylation as a novel therapeutic target to inhibit neuroinflammation and apoptosis after neonatal ischemic brain damage.
Neonatal encephalopathy is associated with high mortality and life-long developmental consequences. Therapeutic options are very limited. We assessed the effects of D-JNKi, a small peptide c-Jun N-terminal kinase (JNK) MAP kinase inhibitor, on neuroinflammation, mitochondrial integrity and neuronal damage in a neonatal rat model of ischemic brain damage. ⋯ We show here for the first time that D-JNKi treatment efficiently protects the neonatal brain against ischemic brain damage and subsequent cognitive and motor impairment. We propose that inhibition of phosphorylation of mitochondrial JNK is a pivotal step in preventing early loss of mitochondrial integrity leading to reduced neuroinflammation and inhibition of apoptotic neuronal loss. Moreover we show the crucial role of upregulation of mitochondrial anti-apoptotic proteins to maintain neuroprotection.
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Neurobiology of disease · Jun 2013
Changes in mouse cognition and hippocampal gene expression observed in a mild physical- and blast-traumatic brain injury.
Warfare has long been associated with traumatic brain injury (TBI) in militarized zones. Common forms of TBI can be caused by a physical insult to the head-brain or by the effects of a high velocity blast shock wave generated by the detonation of an explosive device. While both forms of trauma are distinctly different regarding the mechanism of trauma induction, there are striking similarities in the cognitive and emotional status of survivors. ⋯ While these data highlight similarities in behavioral outcomes after trauma, the divergence in hippocampal transcriptome observed between models suggests that, at the molecular level, the TBIs are quite different. These models may provide tools to help define therapeutic approaches for the treatment of physical- and blast-TBIs. Based upon observations of increasing numbers of personnel displaying TBI related emotional and behavioral changes in militarized zones, the development of efficacious therapies will become a national if not a global priority.
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Neurobiology of disease · Jun 2013
PACAP signaling exerts opposing effects on neuroprotection and neuroinflammation during disease progression in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis.
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic peptide with autocrine neuroprotective and paracrine anti-inflammatory properties in various models of acute neuronal damage and neurodegenerative diseases. Therefore, we examined a possible beneficial role of endogenous PACAP in the superoxide dismutase 1, SOD1(G93A), mouse model of amyotrophic lateral sclerosis (ALS), a lethal neurodegenerative disease particularly affecting somatomotor neurons. In wild-type mice, somatomotor and visceromotor neurons in brain stem and spinal cord were found to express the PACAP specific receptor PAC1, but only visceromotor neurons expressed PACAP as a potential autocrine source of regulation of these receptors. ⋯ Thus, endogenous PACAP may promote microglial cytodestructive functions thought to drive ALS disease progression. This hypothesis was consistent with prolongation of life expectancy and preserved tongue motor function in PACAP-deficient SOD1(G93A) mice, compared to SOD1(G93A) mice. Given the protective role of PACAP expression in visceromotor neurons and the opposing effect on microglial function in SOD1(G93A) mice, both PACAP agonism and antagonism may be promising therapeutic tools for ALS treatment, if stage of disease progression and targeting the specific auto- and paracrine signaling pathways are carefully considered.
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Neurobiology of disease · Apr 2013
Meta AnalysisPredictive neural biomarkers of clinical response in depression: a meta-analysis of functional and structural neuroimaging studies of pharmacological and psychological therapies.
We performed a systematic review and meta-analysis of neural predictors of response to the most commonly used, evidence based treatments in clinical practice, namely pharmacological and psychological therapies. Investigations of medication-free subjects suffering from a current major depressive episode who underwent positron emission tomography (PET) or functional or structural magnetic resonance imaging (MRI) scans prior to the initiation of treatment were reviewed. Results of 20 studies from 15 independent samples were included in the functional imaging meta-analysis and 9 studies from 6 independent samples in the structural neuroimaging meta-analysis. ⋯ To develop clinically relevant, prognostic markers will require high predictive accuracy at the level of the individual. Predicting clinical response will help to stratify patients and to identify at an early stage those patients who may require more intensive or combined therapies. We propose that structural and functional neuroimaging show significant potential for the development of prognostic markers of clinical response in the treatment of depression.
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Neurobiology of disease · Apr 2013
ReviewHow does the brain deal with cumulative stress? A review with focus on developmental stress, HPA axis function and hippocampal structure in humans.
There is evidence that excessive stress exposure of the brain, mediated through the neurotoxic effects of cortisol and possibly neuroinflammation, causes damage to brain structure and function: the glucocorticoid cascade hypothesis. Functional changes of hypothalamic-pituitary-adrenal (HPA) axis as well as alterations in brain structures like the hippocampus have been consistently reported in major depression. However, there has not been a lot of emphasis on bringing findings from studies on early childhood stress, HPA axis functioning and hippocampal imaging together. ⋯ We conclude that a model integrating childhood maltreatment, cortisol abnormalities and hippocampal volume may need to take other factors into account, such as temperament, genetics or the presence of depression; to provide a cohesive explanation of all the findings. Finally, we have to conclude that the cascade hypothesis, mainly based on preclinical studies, has not been translated enough into humans. While there is evidence that early life maltreatment results in structural hippocampal changes and these are in turn more prominent in subjects with higher continuous cortisol secretion it is less clear which role early life maltreatment plays in HPA axis alteration.