What About the Little Ones? Systematic Review of Cognitive and Behavioral Outcomes Following Early TBI.

There is increasing empirical focus on the effects of early traumatic brain injuries (TBI; i.e., before the age of six years) on child development, but this literature has never been synthetized comprehensively. This systematic review aimed to document the cognitive, academic, behavioral, socio-affective, and adaptive consequences of early TBI. Four databases (Medline, PsycNET, CINAHL, PubMed) were systematically searched from 1990 to 2019 using key terms pertaining to TBI and early childhood. Of 12, 153 articles identified in the initial search, 43 were included. Children who sustain early TBI are at-risk for a range of difficulties, which are generally worse when injury is sustained at a younger age, injury severity is moderate to severe, and injury mechanisms are non-accidental. Early childhood is a sensitive period for the emergence and development of new skills and behaviors, and brain disruption during this time is not benign. Research, clinical management, intervention, and prevention efforts should be further developed with consideration of the unique characteristics of the early childhood period.

The PARENT model: a pathway approach for understanding parents' role after early childhood mild traumatic brain injury.

OBJECTIVE: Mild traumatic brain injury (mTBI or "concussion") is a highly prevalent health condition in children, and those under the age of 6 years have the highest rate of Emergency Department presentation for suspected head injuries. The outcome of mTBI is determined by a range of child (injury, biological, functional) and environmental (socio-economic status, parent, family) factors. The aim of this work is to present evidence supporting the central role of parental and familial factors in pediatric mTBI recovery, and to illustrate ways in which parental factors can especially influence the outcome of early mTBI, defined as injuries sustained by infants, toddlers and preschoolers. METHOD: The manuscript first presents a topical review of empirical studies providing evidence that family functioning and parental factors such as their mental or affective state, parenting style, and the quality of their interactions with their child, are affected by and determine the course of recovery after pediatric mTBI. Then, a pathway approach and conceptual model are proposed to illustrate probable scenarios associated with how parents detect and react to their child's post-concussive symptoms and changes in behavior after early mTBI. CONCLUSION: The "Perception, Attribution, and Response after Early Non-inflicted Traumatic Brain Injury" (PARENT) model suggests that parental roles and factors are especially influential in the context of early brain injuries, and that parents' ability to perceive, attribute and respond to the symptoms experienced by their child in a well-adjusted and adaptive manner critically sets the direction and rhythm of the early mTBI recovery process.

The contribution of social cognition in predicting social participation following moderate and severe TBI in youth.

Youth with moderate or severe traumatic brain injury (TBI) are at risk for reduced social participation after the injury, and the contribution of social cognition to these changes in functioning has been little studied. This study aimed to examine social participation and to measure the contribution of social and non-social cognitive functions to social participation impairment in youth (ages 12-21) who sustained moderate or severe TBI. Youth with TBI (n = 23) were compared to typically developing (TD) controls on self- and parent-rated social participation questionnaires. Direct testing of social cognition (mentalising, social knowledge, emotion recognition) and higher order cognitive abilities (intellectual abilities, attention and executive functions) was also conducted. Significant differences were found between the TBI participants and TD controls on social participation measures. Mentalising and problem-solving abilities revealed to be significant correlates of social participation as reported by youth with brain-injury and their parents. Overall, these results corroborate previous findings by showing that social participation is significantly reduced after TBI, and further shows that mentalising, which is not always considered during rehabilitation, is an important contributing factor. In addition to executive function measures, social cognition should therefore be systematically included in assessment following youth TBI for intervention and prevention purposes.

Moral reasoning and decision-making in adolescents who sustain traumatic brain injury.

Objective: Emerging evidence suggests that moral processes are disrupted by traumatic brain injury (TBI). The objective of this study was to explore moral reasoning (MR) and decision-making in adolescents with TBI, and to examine potential associations with global manifestations of social competence.Design: This retrospective, cross-sectional research design compared MR and decision-making in adolescents with mild TBI (n = 20), moderate-severe TBI (n = 23) and typically developing controls (n = 93).Methods: Participants completed a visual task of socio-moral reasoning (SoMoral) and the Index of Empathy for Children and Adolescents. Their parents completed questionnaires documenting their child's behavior (Child Behavior Checklist) and adaptive functioning (Adaptive Behavior Assessment System-Second Edition).Main results: Adolescents with both mild and moderate-severe TBI displayed more immature MR than typically developing peers. Participants with TBI also provided fewer socially adapted decisions. Closer inspection revealed that this difference was apparent only in the mild TBI group. No significant group differences were observed for empathy, behavior or adaptive skills.Conclusions: Sustaining TBI appears to affect adolescents' ability to provide mature moral justifications when faced with moral dilemmas representative of everyday social conflicts. These difficulties do not appear to be associated with behavior problems, reduced empathy, or adaptive functioning.

White matter microstructure predicts longitudinal social cognitive outcomes after paediatric traumatic brain injury: a diffusion tensor imaging study.

BACKGROUND: Deficits in social cognition may be among the most profound and disabling sequelae of paediatric traumatic brain injury (TBI); however, the neuroanatomical correlates of longitudinal outcomes in this domain remain unexplored. This study aimed to characterize social cognitive outcomes longitudinally after paediatric TBI, and to evaluate the use of sub-acute diffusion tensor imaging (DTI) to predict these outcomes. METHODS: The sample included 52 children with mild complex-severe TBI who were assessed on cognitive theory of mind (ToM), pragmatic language and affective ToM at 6- and 24-months post-injury. For comparison, 43 typically developing controls (TDCs) of similar age and sex were recruited. DTI data were acquired sub-acutely (mean = 5.5 weeks post-injury) in a subset of 65 children (TBI = 35; TDC = 30) to evaluate longitudinal prospective relationships between white matter microstructure assessed using Tract-Based Spatial Statistics and social cognitive outcomes. RESULTS: Whole brain voxel-wise analysis revealed significantly higher mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) in the sub-acute TBI group compared with TDC, with differences observed predominantly in the splenium of the corpus callosum (sCC), sagittal stratum (SS), dorsal cingulum (DC), uncinate fasciculus (UF) and middle and superior cerebellar peduncles (MCP & SCP, respectively). Relative to TDCs, children with TBI showed poorer cognitive ToM, affective ToM and pragmatic language at 6-months post-insult, and those deficits were related to abnormal diffusivity of the sCC, SS, DC, UF, MCP and SCP. Moreover, children with TBI showed poorer affective ToM and pragmatic language at 24-months post-injury, and those outcomes were predicted by sub-acute alterations in diffusivity of the DC and MCP. CONCLUSIONS: Abnormal microstructure within frontal-temporal, limbic and cerebro-cerebellar white matter may be a risk factor for long-term social difficulties observed in children with TBI. DTI may have potential to unlock early prognostic markers of long-term social outcomes.

Assessing social cognition: age-related changes in moral reasoning in childhood and adolescence.

OBJECTIVE: There is increasing recognition that socio-cognitive skills, such as moral reasoning (MR), are affected in a wide range of developmental and neuropsychological conditions. However, the lack of appropriate measures available to neuropsychologists poses a challenge for the direct assessment of these skills. This study sought to explore age-related changes in MR using an innovative visual tool and examine the developmental sensitivity of the task. METHOD: To address some of the methodological limitations of traditional measures of MR, a novel, visual task, the Socio-Moral Reasoning Aptitude Level (So-Moral), was used to evaluate MR in 216 healthy participants aged 6-20 years. RESULTS: The findings show a linear increase in MR from childhood to late adolescence with significant group differences between childhood (6-8 years) and preadolescence (9-11 years), and between early adolescence (12-14 years) and middle adolescence (15-17 years). CONCLUSIONS: Interpreted in light of current brain development research, the results highlight age-related changes in MR that offer insight into typical MR development and opportunities for comparisons with clinical populations. The findings also provide evidence of the potential of the So-Moral as a developmentally appropriate measure of MR throughout childhood and adolescence.

A preliminary investigation of moral reasoning and empathy after traumatic brain injury in adolescents.

PRIMARY OBJECTIVE: Traumatic brain injury (TBI) sustained during childhood can affect a number of socio-cognitive skills; however, little attention has focused on the integrity of moral reasoning in the assessment of post-TBI social sequelae and the role of empathy and intelligence on moral maturity. RESEARCH DESIGN: In a quasi-experimental, cross-sectional research design, moral reasoning maturity and empathy in adolescents with mild-to-severe TBI (n = 25) were compared to typically-developing peers (n = 66). METHODS AND PROCEDURES: Participants were administered the So-Moral and So-Mature, tasks of socio-moral reasoning and maturity, the Index of Empathy for Children and Adolescents, the Wechsler Abbreviated Scale of Intelligence and a demographic questionnaire. MAIN OUTCOMES AND RESULTS: Participants with TBI had significantly lower levels of moral reasoning maturity. Further, adolescents with moderate-to-severe TBI had lower levels of empathy. Empathy correlated positively with moral reasoning abilities and, together with intellectual function, predicted a small, but significant proportion of moral reasoning outcome. CONCLUSIONS: Youth who sustained TBI during childhood have poorer moral reasoning abilities than their non-injured peers, potentially placing them at risk for poor social decision-making and socially maladaptive behaviour. This can have a significant impact on long-term social functioning.

Cognitive and psychopathological sequelae of pediatric traumatic brain injury.

Childhood traumatic brain injury (TBI) is a frequent cause of acquired disability in childhood and can have a serious impact on development across the lifespan. The consequences of early TBI vary according to injury severity, with severe injuries usually resulting in more serious physical, cognitive and behavioral sequelae. Both clinical and research reports document residual deficits in a range of skills, including intellectual function, attention, memory, learning, and executive function. In addition, recent investigations suggest that early brain injury also affects psychological and social development and that problems in these domains may increase in the long term postinjury. Together, these deficits affect children's ability to function effectively at school, in the home, and in their social environment, resulting in impaired acquisition of knowledge, psychological and social problems, and overall reduced quality of life. Ultimately, recovery from childhood TBI depends on a range of complex biological, developmental, and psychosocial factors making prognosis difficult to predict. This chapter will detail the cognitive (intellectual, attentional, mnesic, executive, educational, and vocational) and psychopathological (behavioral, adaptive, psychological, social) sequelae of childhood TBI with a particular focus on postinjury recovery patterns in the acute, short-, and long-term phases, as well as into adulthood.

Social function assessment tools for children and adolescents: a systematic review from 1988 to 2010.

Advances in neuroscience have added to the understanding of social functioning which has become an increasing area of focus in the psychology and neuropsychology literature. Given importance of appropriate social functioning to everyday interactions, as well as psychological well-being, accurately identifying and documenting such functions constitute a critical undertaking for both researchers and clinicians in psychology and related health professions. This review aimed to identify available social function assessment tools for children and adolescents using a comprehensive search method. Eighty-six measures were identified. Information on the assessment tools including the theoretical model they are based on, age range, sample used in development, and psychometric information are described. Results will aid researchers, psychologists and other health professionals in the selection of an appropriate tool to assess social function.

Hippocampus, amygdala and global brain changes 10 years after childhood traumatic brain injury.

Traumatic brain injury (TBI) in children results in damage to the developing brain, particularly in severely injured individuals. Little is known, however, of the long-term structural aspects of the brain following childhood TBI. This study investigated the integrity of the brain 10 years post-TBI using magnetic resonance imaging volumetrics in a sample of 49 participants with mild, moderate and severe TBI, evaluated against a normative sample of 20 individuals from a pediatric database with comparable age and gender distribution. Structural integrity was investigated in gray and white matter, and by manually segmenting two regions of interest (hippocampus, amygdala), potentially vulnerable to the effects of childhood TBI. The results indicate that more severe injuries caused a reduction in gray and white brain matter, while all TBI severity levels resulted in increased volumes of cerebrospinal fluid and smaller hippocampal volumes. In addition, enlarged amygdala volumes were detected in severely injured patients compared to their mild and moderate counterparts, suggesting that childhood TBI may disrupt the development of certain brain regions through diffuse pathological changes. The findings highlight the lasting impact of childhood TBI on the brain and the importance of monitoring brain structure in the long-term after early injury.

Cognitive and social profiles in two patients with cobalamin C disease.

Cobalamin C (cblC) disease, an inborn error of vitamin B(12) metabolism, results in neurometabolic, neurochemical and neuroanatomical changes. Little is known of the long-term effects of the disorder on cognition and behaviour in children. Here, the complete neuropsychological profiles of two 12-year-old girls with cblC disease are presented. The two girls were tested longitudinally with standardized neuropsychological tests including intellectual ability, attention and memory, as well as executive, adaptive and behavioural function. The results indicate the presence of intellectual dysfunction, attention problems, and concerns with behavioural aspects of executive function. Both patients demonstrated a pattern of decreasing intellectual function over time, which may reflect a growing developmental gap in comparison with their same age peers. These impairments are in contrast to the relatively spared verbal expression and comprehension abilities, as well as strengths in sociability. The findings highlight a pattern of neuropsychological strengths and weaknesses that may distinguish cblC disease from other inborn errors of metabolism. Overt sociability such as observed in these two patients may actually mask underlying cognitive deficits because the patients appear to function at a more advanced level than that reflected by quantitative assessment of intellectual and cognitive functioning. This is of clinical and functional importance and suggests that accurate determination of cognitive, adaptive and social abilities necessitates an in-depth and broad evaluation. The presence of significant intellectual and cognitive deficits also underscores the need to document and monitor cognitive development in children with cblC disease and to consider remediative and adaptive learning strategies.

Cognitive, behavioural and adaptive profiles of children with glutaric aciduria type I detected through newborn screening.

BACKGROUND: Glutaric aciduria type I (GA I) is an autosomal recessive disorder of lysine and tryptophan metabolism due to a deficiency in glutaryl-CoA dehydrogenase activity. Recent reports suggest that early diagnosis through newborn screening and initiation of preventive therapy result in improved functional outcome; however, detailed neuropsychological profiles of children with GA I are seldom reported and thus the impact of the disease on cognition, motor abilities and behaviour remains uncertain. METHOD: We present detailed neuropsychological profiles of three children who were diagnosed with GA I through newborn screening and treated from early age, and one asymptomatic patient diagnosed through cascade screening. A comprehensive battery of standardized tests was administered including measures of intellectual function, attention/memory, executive function, motor skills, speech/language, as well as behavioural and adaptive skills. RESULTS: The results reveal overall average cognitive outcomes; however, subtle, but significant, fine motor and articulation deficits were observed. The results are discussed with regard to potential links between fine motor deficits and speech impairments in children with GA I. Such difficulties can impact on the child's ability to engage in academic, leisure and daily activities. CONCLUSIONS: These findings highlight the importance of in-depth assessments of all aspects of neuropsychological function in patients with GA I and provide a basis for future neuropsychological assessment in similar groups of children. In spite of relatively preserved overall functioning, using a broad range of sensitive cognitive and motor measures facilitates the detection of subtle deficits, and allows for planning of early and adequate therapeutic interventions.

Neural substrates of cognitive skill learning in Parkinson's disease.

While cognitive skill learning is normally acquired implicitly through frontostriatal circuitry in healthy individuals, neuroimaging studies suggest that patients with Parkinson's disease (PD) do so by activating alternate, intact brain areas associated with explicit memory processing. To further test this hypothesis, 10 patients with PD and 12 healthy controls were tested on a modified, learning version of the Tower of London task while undergoing positron emission tomography at four different time points over the course of learning. Despite having less accurate problem solving abilities than controls, PD patients were able to acquire the skill learning task. However, as compared to controls, they maintained higher levels of cerebral blood flow activity in the dorsolateral prefrontal cortex and hippocampus and showed an increase in activity in the frontopolar cortex and posterior cingulate over the course of learning. These findings reflect a shift to the explicit memory system in PD patients, enabling them to learn this cognitive skill, which is normally acquired by control subjects using implicit learning strategies and frontostriatal circuitry.

Dynamic functional changes associated with cognitive skill learning of an adapted version of the Tower of London task.

In this study, we used a modified version of the Tower of London (TOL) planning task, in conjunction with positron emission tomography, to examine the neural substrates mediating cognitive skill learning. Twelve healthy, right-handed participants solved a total of 90 different TOL problems. They were scanned on four occasions during the fast learning stage as well as in a condition designed to control for internally guided movements. Practice of the TOL task resulted in a significant decrease in planning, execution, and total time taken to solve the problems. Consistent with the results of previous studies, early performance of the TOL task was associated with increased blood flow activity in the dorsolateral prefrontal, orbitofrontal, and parietal cortices on the left, as well as in the caudate nucleus, cerebellum, and premotor cortex, bilaterally. Interestingly, however, activity in the left caudate nucleus was maintained from the beginning to the end of the learning process, suggesting that this structure plays a role in this type of cognitive skill learning. In addition, correlational analyses revealed that improved performance on the TOL task was associated with a significant decrease of activity in the medial orbitofrontal and frontopolar cortices over the course of learning, areas thought to be involved in decision making, guessing, and monitoring of feedback information. In sum, the results lend further support to the idea that the learning of cognitive skills requiring planning and working memory capacities is mediated through a fronto-striatal network.

Cyclooxygenase-2 in human and experimental ischemic proliferative retinopathy.

BACKGROUND: Intravitreal neovascular diseases, as in ischemic retinopathies, are a major cause of blindness. Because inflammatory mechanisms influence vitreal neovascularization and cyclooxygenase (COX)-2 promotes tumor angiogenesis, we investigated the role of COX-2 in ischemic proliferative retinopathy. METHODS AND RESULTS: We describe here that COX-2 is induced in retinal astrocytes in human diabetic retinopathy, in the murine and rat model of ischemic proliferative retinopathy in vivo, and in hypoxic astrocytes in vitro. Specific COX-2 but not COX-1 inhibitors prevented intravitreal neovascularization, whereas prostaglandin E2, mainly via its prostaglandin E receptor 3 (EP3), exacerbated neovascularization. COX-2 inhibition induced an upregulation of thrombospondin-1 and its CD36 receptor, consistent with the observed antiangiogenic effects of COX-2 inhibition; EP3 stimulation reversed effects of COX-2 inhibitors on thrombospondin-1 and CD36. CONCLUSIONS: These findings point to an important role for COX-2 in ischemic proliferative retinopathy, as in diabetes.

Prostanoid receptors: ontogeny and implications in vascular physiology.

Prostanoids exert significant effects on circulatory beds. They play a role in the response of the vasculature to adjustments in perfusion pressure and oxygen and carbon dioxide tension, and they mediate the actions of numerous factors. The role of prostanoids in governing circulation of the perinate is suggested to surpass that in the adult. Prostanoids are abundantly generated in the perinate. They have been implicated in autoregulation of blood flow as studied in brain and eyes. Prostaglandins are also dominant regulators of ductus arteriosus tone. The effects of these autacoids are mediated through specific G protein-coupled receptors. In addition to the pharmacological characterization of the prostanoid receptors, important advances in understanding the biology of these receptors have been made in the last decade. Their cloning and the development of animals with disrupted genes of these receptors have been very informative. The involvement of prostanoid receptors in the developing subject, especially on brain and ocular vasculature and on ductus arteriosus, has also begun to be investigated; the expression of these receptors changes with development. Some but not all of the ontogenic changes in these receptors are attributed to homologous regulation. Interestingly, in the process of elucidating their effects, functional perinuclear prostaglandin E2 receptors have been uncovered. This article reviews prostanoid receptors and addresses implications on the developing subject with attention to vascular physiology.

2,3-Dinor-5,6-dihydro-15-F(2t)-isoprostane: a bioactive prostanoid metabolite.

15-F(2t)-isoprostane (15-F(2t)-IsoP), also termed 8-isoprostaglandin F(2alpha), is one of a series of prostanoids formed by free radical-mediated peroxidation of arachidonic acid and exerts potent biological actions such as vasoconstriction. We recently demonstrated that 15-F(2t)-IsoP is metabolized in humans to a major metabolite, 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP (15-F(2t)-IsoP-M). 15-F(2t)-IsoP-M can also potentially be formed as a product of free radical-induced oxidation of the low abundance fatty acid gamma-linolenic acid. We confirmed that 15-F(2t)-IsoP-M is generated during oxidation of gamma-linolenic acid and explored whether it may exhibit biological activity. 15-F(2t)-IsoP-M caused marked constriction of porcine surface retinal and intraparenchymal brain microvessels, comparable to that observed with 15-F(2t)-IsoP. These effects were associated with increased thromboxane A(2) (TXA(2)) formation and were virtually abolished by TXA(2)-synthase and -receptor inhibitors (CGS-12970 and L-670596). Vasoconstriction induced by either 15-F(2t)-IsoP or 15-F(2t)-IsoP-M on perfused ocular choroid was also abrogated by TXA(2)-synthase inhibition as well as by removal of endothelium. Similar to 15-F(2t)-IsoP, 15-F(2t)-IsoP-M evoked vasoconstriction and TXA(2) generation by activating Ca(2+) influx from nonvoltage-gated channels (SK&F96365 sensitive) in the retina and from both nonvoltage- and N-type voltage-gated Ca(2+) channels (omega-conotoxin MVIIA sensitive), respectively, in brain endothelial and astroglial cells; smooth muscle cells were unresponsive to both agents. Cross-desensitization experiments further suggest that 15-F(2t)-IsoP and 15-F(2t)-IsoP-M act on the same receptor mechanism. Findings reveal a novel concept by which a beta-oxidation metabolite of 15-F(2t)-IsoP that can also be formed by nonenzymatic oxidation of gamma-linolenic acid is equivalently bioactive to 15-F(2t)-IsoP and may prolong the vascular actions of F(2)-IsoPs.

Role of thromboxane in retinal microvascular degeneration in oxygen-induced retinopathy.

Microvascular degeneration is an important event in oxygen-induced retinopathy (OIR), a model of retinopathy of prematurity. Because oxidant stress abundantly generates thromboxane A2 (TxA2), we tested whether TxA2 plays a role in retinal vasoobliteration of OIR and contributes to such vascular degeneration by direct endothelial cytotoxicity. Hyperoxia-induced retinal vasoobliteration in rat pups (80% O2 exposure from postnatal days 5-14) was associated with increased TxB2 generation and was significantly prevented by TxA2 synthase inhibitor CGS-12970 (10 mg x kg(-1) x day(-1)) or TxA2-receptor antagonist CGS-22652 (10 mg x kg(-1) x day(-1)). TxA2 mimetics U-46619 (EC50 50 nM) and I-BOP (EC50 5 nM) caused a time- and concentration-dependent cell death of neuroretinovascular endothelial cells from rats as well as newborn pigs but not of smooth muscle and astroglial cells; other prostanoids did not cause cell death. The peroxidation product 8-iso-PGF2, which is generated in OIR, stimulated TxA2 formation by endothelial cells and triggered cell death; these effects were markedly diminished by CGS-12970. TxA2-dependent neuroretinovascular endothelial cell death was mostly by necrosis and to a lesser extent by apoptosis. The data identify an important role for TxA2 in vasoobliteration of OIR and unveil a so far unknown function for TxA2 in directly triggering neuroretinal microvascular endothelial cell death. These effects of TxA2 might participate in other ischemic neurovascular injuries.

Neurosteroids and reward: allopregnanolone produces a conditioned place aversion in rats.

The neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone) has been reported to have rewarding properties in mice tested for place conditioning. Another study found that allopregnanolone reduced dopamine (DA) output in the nucleus accumbens (NAc) of rats. As many rewarding stimuli increase accumbens DA, these results may appear contradictory. Thus, the present study examined the rewarding properties of allopregnanolone in rats tested for place conditioning using an unbiased conditioning procedure. In control studies, a place preference was observed following conditioning with intraperitoneal (2.0 mg/kg) or intracerebroventricular (i.c.v.) (100 microg/0.5 microl) amphetamine. Conditioning with i.c.v. allopregnanolone produced a significant aversion at a dose of 5.0 microg (in 5.0 microl) and a near aversion at 25.0 microg (in 8.3 microl); doses of 0 microg (i.e., vehicle alone, in 10 microl) or 30.0 microg (in 10 microl) produced little effect on place preference. During conditioning, locomotor activity was stimulated by amphetamine using either route of administration, but allopregnanolone had no significant main effect on locomotor activity. Thus, there was a dissociation between the effects of drugs on locomotor activity vs. place conditioning. Results show that i.c.v. amphetamine produces a place preference, whereas allopregnanolone produces either no effect or an aversion, depending on the dose.

Prolonged hypercapnia-evoked cerebral hyperemia via K(+) channel- and prostaglandin E(2)-dependent endothelial nitric oxide synthase induction.

Mechanisms for secondary sustained increase in cerebral blood flow (CBF) during prolonged hypercapnia are unknown. We show that induction of endothelial NO synthase (eNOS) by an increase in prostaglandins (PGs) contributes to the secondary CBF increase during hypercapnic acidosis. Ventilation of pigs with 6% CO(2) (PaCO(2 approximately)65 mm Hg; pH approximately 7.2) caused a approximately 2.5-fold increase in CBF at 30 minutes, which declined to basal values at 3 hours and gradually rose again at 6 and 8 hours; the latter increase was associated with PG elevation, nitrite formation, eNOS mRNA expression, and in situ NO synthase (NOS) reactivity (NADPH-diaphorase staining). Subjecting free-floating brain sections to acidotic conditions increased eNOS expression, the time course of which was similar to that of CBF increase. Treatment of pigs with the cyclooxygenase inhibitor diclofenac or the NOS inhibitor Nomega-nitro-L-arginine blunted the initial rise and prevented the secondary CBF increase during hypercapnic acidosis; neuronal NOS blockers 1-(2-trifluoromethylphenyl) imidazole and 3-bromo-7-nitroindazole were ineffective. Diclofenac abolished the hypercapnia-induced rise in cerebrovascular nitrite production, eNOS mRNA expression, and NADPH-diaphorase reactivity. Acidosis (pH approximately 7.15, PCO(2 approximately )40 mm Hg; 6 hours) produced similar increases in prostaglandin E(2) (PGE(2)) and eNOS mRNA levels in isolated brain microvessels and in NADPH-diaphorase reactivity of brain microvasculature; these changes were prevented by diclofenac, by the receptor-operated Ca(2+) channel blocker SK&F96365, and by the K(ATP) channel blocker glybenclamide. Acidosis increased Ca(2+) transients in brain endothelial cells, which were blocked by glybenclamide and SK&F96365 but not by diclofenac. Increased PG-related eNOS mRNA and NO-dependent vasorelaxation to substance P was detected as well in rat brain exposed to 6 hours of hypercapnia. PGE(2) was the only major prostanoid that modulated brain eNOS expression during acidosis. Thus, in prolonged hypercapnic acidosis, the secondary CBF rise is closely associated with induction of eNOS expression; this seems to be mediated by PGE(2) generated by a K(ATP) and Ca(2+) channel-dependent process.