ABSTRACT
N-myc downstream-regulated gene 2 (Ndrg2) is a differentiation- and stress-associated molecule predominantly expressed in astrocytes in the CNS. In this study, we examined the expression and the role of Ndrg2 after cortical stab injury. We observed that Ndrg2 expression was elevated in astrocytes surrounding the wounded area as early as day 1 after injury in wild-type mice. Deletion of Ndrg2 resulted in lower induction of reactive astroglial and microglial markers in the injured cortex. Histological analysis showed reduced levels of hypertrophic changes in astrocytes, accumulation of microglia, and neuronal death in Ndrg2(-/-) mice after injury. Furthermore, activation of the IL-6/signal transducer and activator of transcription 3 (STAT3) pathway, including the expression of IL-6 family cytokines and phosphorylation of STAT3, was markedly reduced in Ndrg2(-/-) mice after injury. In a culture system, both of Il6 and Gfap were up-regulated in wild-type astrocytes treated with forskolin. Deletion of Ndrg2 attenuated induction of these genes, but did not alter proliferation or migration of astrocytes. Adenovirus-mediated reexpression of Ndrg2 rescued the reduction of IL-6 expression after forskolin stimulation. These findings suggest that Ndrg2 plays a key role in reactive astrogliosis after cortical stab injury through a mechanism involving the positive regulation of IL-6/STAT3 signaling.
Subject(s)
Astrocytes/pathology , Brain Injuries/genetics , Brain Injuries/pathology , Cerebral Cortex/injuries , Gliosis/genetics , Gliosis/pathology , Head Injuries, Penetrating/genetics , Head Injuries, Penetrating/pathology , Inflammation/genetics , Inflammation/pathology , Proteins/genetics , Proteins/physiology , Wounds, Stab/genetics , Wounds, Stab/pathology , Adaptor Proteins, Signal Transducing , Animals , Cell Death/genetics , Cell Death/physiology , Cells, Cultured , Colforsin , Dependovirus/genetics , Enzyme-Linked Immunosorbent Assay , Gene Deletion , Glial Fibrillary Acidic Protein/biosynthesis , Glial Fibrillary Acidic Protein/metabolism , Immunohistochemistry , Interleukin-6/physiology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Polymerase Chain Reaction , Real-Time Polymerase Chain Reaction , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/physiology , Signal TransductionABSTRACT
The past few years have seen an increase in the clinical awareness of post-traumatic stress disorder (PTSD), one of the most disabling and least understood behavioral disorders. Although the biological bases of PTSD are poorly understood, fatty-acid amide hydrolase (FAAH) activity has been linked with arousability and aversive-memories extinction, that is, two key features of PTSD. In this study, we investigated the association between the FAAH genetic polymorphisms and PTSD development and maintenance. We assessed PTSD frequency in a group of male Vietnam war veterans who suffered combat-related penetrating traumatic brain injury, that is, a relatively homogeneous population regarding the nature of the events that led to PTSD. We showed that rs2295633, a single-nucleotide polymorphism of FAAH, was significantly associated with PTSD diagnosis in subjects without lesions in the ventromedial prefrontal cortex. Moreover, the presence of the C allele was associated with more severe re-experiencing of trauma and more negative reported childhood experiences. In conclusion, our data suggest that FAAH has an important role in PTSD through modulation of aversive memories and point to both a novel therapeutic target and a possible risk marker for this condition.
Subject(s)
Alleles , Amidohydrolases/genetics , Combat Disorders/genetics , Genetic Predisposition to Disease/genetics , Head Injuries, Penetrating/genetics , Polymorphism, Genetic/genetics , Polymorphism, Single Nucleotide/genetics , Stress Disorders, Post-Traumatic/genetics , Veterans/psychology , Vietnam Conflict , Adolescent , Adult , Aged , Child , Child Abuse/psychology , Combat Disorders/diagnosis , Combat Disorders/epidemiology , Combat Disorders/psychology , Cross-Sectional Studies , Defense Mechanisms , Genotype , Head Injuries, Penetrating/diagnosis , Head Injuries, Penetrating/epidemiology , Humans , Image Interpretation, Computer-Assisted , Life Change Events , Male , Mental Recall/physiology , Middle Aged , Prefrontal Cortex/injuries , Stress Disorders, Post-Traumatic/diagnosis , Stress Disorders, Post-Traumatic/epidemiology , Stress Disorders, Post-Traumatic/psychology , Tomography, X-Ray ComputedABSTRACT
OBJECTIVE: This study investigates the interaction between brain lesion location and monoamine oxidase A (MAO-A) in the genesis of aggression in patients with penetrating traumatic brain injury (PTBI). METHODS: We enrolled 155 patients with PTBI and 42 controls drawn from the Vietnam Head Injury Study registry. Patients with PTBI were divided according to lesion localization (prefrontal cortex [PFC] vs non-PFC) and were genotyped for the MAO-A polymorphism linked to low and high transcriptional activity. Aggression was assessed with the aggression/agitation subscale of the Neuropsychiatric Inventory (NPI-a). RESULTS: Patients with the highest levels of aggression preferentially presented lesions in PFC territories. A significant interaction between MAO-A transcriptional activity and lesion localization on aggression was revealed. In the control group, carriers of the low-activity allele demonstrated higher aggression than high-activity allele carriers. In the PFC lesion group, no significant differences in aggression were observed between carriers of the 2 MAO-A alleles, whereas in the non-PFC lesion group higher aggression was observed in the high-activity allele than in the low-activity allele carriers. Higher NPI-a scores were linked to more severe childhood psychological traumatic experiences and posttraumatic stress disorder symptomatology in the control and non-PFC lesion groups but not in the PFC lesion group. CONCLUSIONS: Lesion location and MAO-A genotype interact in mediating aggression in PTBI. Importantly, PFC integrity is necessary for modulation of aggressive behaviors by genetic susceptibilities and traumatic experiences. Potentially, lesion localization and MAO-A genotype data could be combined to develop risk-stratification algorithms and individualized treatments for aggression in PTBI.
Subject(s)
Aggression/physiology , Brain Injuries/psychology , Head Injuries, Penetrating/psychology , Monoamine Oxidase/genetics , Prefrontal Cortex/injuries , Alleles , Brain Injuries/complications , Brain Injuries/genetics , Brain Injuries/pathology , Brain Mapping/methods , Genotype , Head Injuries, Penetrating/complications , Head Injuries, Penetrating/genetics , Head Injuries, Penetrating/pathology , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Polymorphism, Genetic , Prefrontal Cortex/pathology , Psychiatric Status Rating Scales , Stress Disorders, Post-Traumatic/complications , Stress Disorders, Post-Traumatic/diagnosisABSTRACT
Los macroadenomas hipofisarios (de diámetro superior a 10 mm) son poco frecuentes como hallazgos casuales, y su manejo diagnóstico y terapéutico no está bien definido. Los criterios más habituales para el tratamiento neuroquirúrgico son la afectación del campo visual, la hipersecreción de hormonas distintas a la prolactina, la constatación de crecimiento, o la apoplejía no silente. Presentamos dos casos en los que la indicación de cirugía se estableció en función de la edad -joven- de la paciente (caso número uno) y de la afectación del eje gonadal en un varón no subsidiario de tratamiento androgénico (caso número dos). Se discute el beneficio de incluir tales indicaciones quirúrgicas en el protocolo de evaluación de estas lesiones (AU)
Pituitary macroadenomas (more than 10 mm in diameter) are infrequent as casual findings and optimal management strategy for these tumours has not been established. Neurosurgical approach must be always considered in patients with visual field defects or with hormone-secreting adenomas (but prolactinoma), and in those with evidence of lesion's growth or if clinical pituitary apoplexy occurs. We present two cases in which surgical indication was based on patient's young age (case number one), and on hypogonadal status, in a male patient not suitable of androgen substitution (case number two). We also discuss the benefits of including such unusual indications for neurosurgical treatment into the incidentally discovered pituitary macroadenomas evaluation strategy (AU)
