Epileptic manifestations induced by midazolam in the neonatal period

Montenegro, Maria Augusta; Guerreiro, Marilisa M.; Caldas, Jamil Pedro de Siqueira; Moura-Ribeiro, Maria Valeriana Leme de; Guerreiro, Carlos A. M.

doi:10.1590/s0004-282x2001000200018

Cited by 23 publications

(13 citation statements)

References 7 publications

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“…It is tempting to associate such findings with occasional reports of ictogenic effects of GABA A -acting drugs, like midazolam in low-birth-weight premature neonates (Montenegro et al 2001;Ng et al 2002). These are only sporadic reports and, at present, GABA A -acting drugs, including benzodiazepines and barbiturates still remain the first line treatment for neonatal seizures.…”

Section: Sex-specific Gaba a Signaling: Clinical Implicationsmentioning

confidence: 99%

Sexually dimorphic expression of KCC2 and GABA function

Galanopoulou

2008

Epilepsy Research

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GABA(A) receptors have an age-adapted function in the brain. During early development, they mediate depolarizing effects, which result in activation of calcium-sensitive signaling processes that are important for the differentiation of the brain. In more mature stages of development and in adults, GABA(A) receptors acquire their classical hyperpolarizing signaling. The switch from depolarizing to hyperpolarizing GABA(A)-ergic signaling is triggered through the developmental shift in the balance of chloride cotransporters that either increase (i.e. NKCC1) or decrease (i.e. KCC2) intracellular chloride. The maturation of GABA(A) signaling follows sex-specific patterns, which correlate with the developmental expression profiles of chloride cotransporters. This has first been demonstrated in the substantia nigra, where the switch occurs earlier in females than in males. As a result, there are sensitive periods during development when drugs or conditions that activate GABA(A) receptors mediate different transcriptional effects in males and females. Furthermore, neurons with depolarizing or hyperpolarizing GABA(A)-ergic signaling respond differently to neurotrophic factors like estrogens. Consequently, during sensitive developmental periods, GABA(A) receptors may act as broadcasters of sexually differentiating signals, promoting gender-appropriate brain development. This has particular implications in epilepsy, where both the pathophysiology and treatment of epileptic seizures involve GABA(A) receptor activation. It is important therefore to study separately the effects of these factors not only on the course of epilepsy but also design new treatments that may not necessarily disturb the gender-appropriate brain development.

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Section: Sex-specific Gaba a Signaling: Clinical Implicationsmentioning

confidence: 99%

Sexually dimorphic expression of KCC2 and GABA function

Galanopoulou

2008

Epilepsy Research

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“…GABA is depolarizing in the neonatal life and it stays depolarizing for longer developmental periods in the male brain than in females [17, 29–33]. Paradoxical exacerbation of seizures by GABA-acting drugs has been reported in newborns, especially in low weight premature babies [34]. GABA-acting drugs, such as benzodiazepines and barbiturates, however, still remain the mainstay of treatments for neonatal seizures, even if they may not always be as effective in newborn human babies as in older patients [21, 35–39].…”

Section: The Immaturity Of Gabaaergic Systems As An Age and Sex-spmentioning

confidence: 99%

Altered GABA Signaling in Early Life Epilepsies

Briggs

Galanopoulou

2011

Neural Plasticity

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The incidence of seizures is particularly high in the early ages of life. The immaturity of inhibitory systems, such as GABA, during normal brain development and its further dysregulation under pathological conditions that predispose to seizures have been speculated to play a major role in facilitating seizures. Seizures can further impair or disrupt GABAA signaling by reshuffling the subunit composition of its receptors or causing aberrant reappearance of depolarizing or hyperpolarizing GABAA receptor currents. Such effects may not result in epileptogenesis as frequently as they do in adults. Given the central role of GABAA signaling in brain function and development, perturbation of its physiological role may interfere with neuronal morphology, differentiation, and connectivity, manifesting as cognitive or neurodevelopmental deficits. The current GABAergic antiepileptic drugs, while often effective for adults, are not always capable of stopping seizures and preventing their sequelae in neonates. Recent studies have explored the therapeutic potential of chloride cotransporter inhibitors, such as bumetanide, as adjunctive therapies of neonatal seizures. However, more needs to be known so as to develop therapies capable of stopping seizures while preserving the age- and sex-appropriate development of the brain.

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“…Excessive calcium influx, which can occur following over-activation of the GABA A receptor during this time period, results in cell death (Orrenius et al, 2003;Paschen, 2003;Siesjo, 1994;Tymianski, 1996). Work in fetal primates (Khazipov et al, 2001), along with data in humans documenting that benzodiazepines (GABA A receptor agonists) can exacerbate seizures in premature and newborn human infants (Guerrini et al, 1998;Montenegro et al, 2001;Ng et al, 2002), has verified that the "excitatory" actions of developmental GABA A receptor activation are not relegated to non-human species. Given this information, an investigation of the anatomical and behavioral consequences of early anesthetic exposure is warranted.…”

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confidence: 99%

Response to neonatal anesthesia: Effect of sex on anatomical and behavioral outcome

2008

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Numerous studies have documented the consequences of exposure to anesthesia in models of term and post-term infants, evaluating the incidence of cell loss, physiological alterations and cognitive dysfunction. However, surprisingly few studies have investigated the effect of anesthetic exposure on outcomes in newborn rodents, the developmental equivalent of premature human infants. This is critical given that one out of every eight babies born in the United States is premature, with an increased prevalence of surgical procedures required in these individuals. Also, no studies have investigated if the genetic sex of the individual influences the response to neonatal anesthesia. Using the newborn rat as the developmental equivalent of the premature human, we documented the effect of a single bout of exposure to either the inhalant isoflurane or the injectable barbiturate phenobarbital on hippocampal anatomy, hippocampal dependent behavioral performance and normal developmental endpoints in male and female rats. While both forms of anesthesia led to significant decrements in cognitive abilities, along with a significant reduction in volume and neuron number in the hippocampus in adulthood, the decrements were significantly greater in males than in females. Interestingly, the deleterious effects of anesthesia were manifest on developmental measures including surface righting and forelimb grasp, but were not evident on basic physiological parameters including body weight or suckling. These findings point to the hazardous effects of exposure to anesthesia on the developing central nervous system and the particular sensitivity of males to deficits.

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Epileptic manifestations induced by midazolam in the neonatal period

Cited by 23 publications

References 7 publications

Sexually dimorphic expression of KCC2 and GABA function

Sexually dimorphic expression of KCC2 and GABA function

Altered GABA Signaling in Early Life Epilepsies

Response to neonatal anesthesia: Effect of sex on anatomical and behavioral outcome

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