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 Table of Contents  
REVIEW ARTICLE
Year : 2016  |  Volume : 2  |  Issue : 2  |  Page : 71-78

Neuronal apoptosis of the developing brain: Influence of anesthetics


Department of Anesthesiology and Intensive Care, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India

Date of Web Publication12-Apr-2017

Correspondence Address:
Padmaja Durga
Department of Anesthesiology and Intensive Care, Nizam's Institute of Medical Sciences, Hyderabad, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2395-4264.204409

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  Abstract 


Surgeries and multiple procedures are undertaken on millions of children all over the world which involves exposure of these children to anesthetics during the stage of brain development. There is an increasing concern regarding the risk of anaesthetic neurotoxicity in children. Evidence has shown that exposure to all commonly used anaesthetics and sedatives can cause neurodegeneration in the developing brain with the possible exception of α2-adrenergic agonists. Anaesthetic effects on the brain during its growth spurt can initiate a cascade of alterations in neurodevelopment which have been detected structurally or functionally in preclinical experiments. The studies are ongoing to gather clinical evidence.

Keywords: Anesthetic exposure, anesthetic drugs, neurodevelopement, neurotoxicity, apoptosis


How to cite this article:
Durga P. Neuronal apoptosis of the developing brain: Influence of anesthetics. Indian J Cereb Palsy 2016;2:71-8

How to cite this URL:
Durga P. Neuronal apoptosis of the developing brain: Influence of anesthetics. Indian J Cereb Palsy [serial online] 2016 [cited 2017 Oct 19];2:71-8. Available from: http://www.ijcpjournal.org/text.asp?2016/2/2/71/204409




  Introduction Top


There is an increasing concern regarding the risk of anesthetic neurotoxicity in children. Compelling evidence has shown that exposure to anesthetics can cause neurodegeneration in the mammalian developing brain, but the basis of this is not clear. Neurotoxicity induced by exposure to anesthetics in early life involves neuroapoptosis and impairment of neurodevelopmental processes such as neurogenesis, synaptogenesis, and immature glial development. These effects may subsequently contribute to behavior abnormalities in later life.


  Why Is Developing Brain Vulnerable to Neuronal Toxicity? Top


The mammalian brain contains a population of neurons that are continuously generated from late embryogenesis through adulthood after the generation of almost all other neuronal types. Perinatal life and early childhood are the most intensive periods of brain development, during which the fetus, infants, and children undergo an eruption in neuronal proliferation, differentiation, synaptogenesis, and rapid development of dendrites to establish the complicated networks of the central nervous system. However, environmental stresses can greatly impair brain development, not only before but also after birth. For example, children who require surgical interventions are exposed to many stressors including mental, pain, inflammatory, and anesthesia, which could affect brain and behavioral development. There are many trophic factors and receptors involved in development. Crucially, the morphology and function of receptors involved in development changes with age. This explains why particular drug effects may be observed during specific developmental periods.

The number of synapses and neurons halves during development. The loss of neurons occurs through apoptosis. Apoptosis, or cell suicide, is an organized energy-consuming process, by which “unwanted” cells are removed from the organ. Apoptosis involves chromatin aggregation, condensation of cellular organelles, and development of apoptotic bodies that are readily consumed by phagocytosis. Apoptosis may be triggered through two pathways: intrinsic and extrinsic. Both pathways, however, share a final common sequence that identifies an important marker of apoptosis: activation of the enzyme caspase 3.[1] Many factors can trigger apoptosis including normal growth and development, diseases, and anesthetics. General anesthetics not only induce neuroapoptosis but also affect neurodevelopmental processes at the peak of synaptogenesis through certain cellular mechanisms. Evidence is mounting that anesthetic exposure leads to a number of molecular, cellular, and behavioral changes in the developing brain, and these effects can be harmful and long-lasting.[2]


  Molecular Mechanisms Top


Neuroapoptosis

Apoptosis can occur physiologically in the mammalian brain during the period of the growth spurt. Since disruption of physiological processes may result in neurodevelopmental disorders, anesthetics potentially damage the developing brain by affecting neurogenesis, cell migration, or cell survival through different intracellular signaling pathways in prenatal cortical and hippocampal neurons. Although the underlying molecular mechanisms of anesthetic neurotoxicity are not completely understood, mitochondrial dysfunction, altered calcium homeostasis, and apoptosis-related proteins have been implicated. Increased cytosolic free calcium [Ca 2+] and lowered mitochondrial transmembrane potential after anesthetics exposure significantly decrease the expression of antiapoptotic protein (Bcl-2), increase expression of proapoptotic protein Bax, and stimulate the release of cytochrome-c from mitochondria in primary rat cortical neurons. Other mechanisms include activation of microglia and astrocytes, causing the production of pro-inflammatory factors, and upregulation of nicotinamide adenine dinucleotide phosphate oxidase thus leading to generation of reactive oxygen species (ROS) and disruption of mitochondrial membrane potential.[3]

N-methyl-D-aspartate receptors and gamma-aminobutyric acid type A receptors

The gamma-aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) receptors are indirectly involved in the balance of activity and thus the generation of trophic factors that drive differentiation, growth, and apoptosis. GABA and NMDA receptors are directly involved in cell proliferation, migration, cell survival, and dendritic maturation.[4] Anesthetics act on GABA and NMDA receptors. The toxic effects of NMDA receptor antagonists on the immature brain have been extensively explored. Ketamine, an NMDA receptor antagonist, is commonly used for pediatric anesthesia and analgesia. Although clinical evidence for ketamine neurotoxicity in children undergoing is inconclusive,[5],[6],[7],[8] recent experimental studies have reported that ketamine causes neuronal cell death in developing animals.[9],[10] Ketamine may cause a compensatory upregulation of NMDA receptors, subsequently triggering expression of apoptosis-related genes in the developing neurons.

Neuroscientists have realized GABA type A (GABAA) receptor agonists can affect neurodevelopment. Currently, several anesthetics, sedatives, or anticonvulsants used clinically acting on GABAA receptor agonists. They could suppress postnatal neurogenesis trigger widespread apoptotic cell death in developing rodent brain, eventually resulting in long-term neurobehavioral impairment.[11],[12]

Mitochondrial perturbations

Mitochondria also play essential roles in controlling apoptosis. Injured mitochondria could be a significant source of ROS which, if not scavenged properly, may cause excessive lipid peroxidation and damage to cellular membranes. Anesthesia can impair mitochondrial morphogenesis, integrity, and function at the peak of synaptogenesis, and this mitochondrial impairment may be central in anesthetic-induced acute neuroapoptosis and cognitive abnormalities in later life. Anesthetics induce neurotoxicity through opening of the mitochondrial permeability transition pore, elevation in ROS levels, reduction in mitochondrial membrane potential and adenosine-5'-triphosphate production, and activation of caspase-3.[13],[14],[15],[16] Peri-anesthesia treatment with an ROS scavenger or mitochondrial protectant prevented anesthesia-induced cognitive impairment.

Dysregulation of intracellular Ca 2+ homeostasis

Loss of loss of calcium regulation promotes several events including mitochondrial dysfunction and cytochrome C release, increased active caspase-3, growth cone collapse, as well as reduced neurite length and complexity. Downstream of calcium dysregulation is changes in expression of proteins related to the cytoskeleton, synapse, production of neurotransmitters, or calcium buffering. Volatile anesthetics including isoflurane and sevoflurane could induce intracellular calcium overload, which increases ROS and nitric oxide levels that could result in neuroapoptosis. Isoflurane can enhance the GABA-induced (Ca 2+) increase and potentiate GABAA receptor-mediated synaptic voltage-dependent calcium channels.[11] Calcium oscillations increase CaMK II levels which would then promote neuronal synaptic plasticity and synapsin levels. A persistent intracellular Ca 2+ concentration not only interferes with Ca 2+ oscillation, which would affect neuronal synaptogenesis, but also leads to neuronal apoptosis.[17]

Neuroinflammatory pathway

Recent findings suggest that neuroinflammatory mediators such as cytokines may be involved in a number of key steps in the pathological cascade of events, leading to anesthetic-induced neuronal injury.[18],[19] Nociceptive stimulation (e.g., surgical incision) with prolonged anesthesia exposure produces significantly more apoptosis than prolonged anesthesia alone in neonates during the synaptogenic period.[20] Both anesthesia and surgery can induce cytokines release in the central nervous system, leading to deleterious neurodevelopmental effects.

The brain-derived neurotrophic factor pathway

Neurotrophins such as brain-derived neurotrophic factor (BDNF) are chemicals of central importance in the regulation of the survival, differentiation, and maintenance of functions as synaptic plasticity in the developing brain. Evidence has shown that general anesthetics induce neuroapoptotic damage in the developing brain, at least in part through the BDNF-modulated apoptotic cascade.[21],[22]

Other cellular processes in neurodevelopment

Neurogenesis

Anesthetics can cause the inhibition on maturation and proliferation of neuronal progenitor cells,[23],[24] decrease the pool of neural stem cells, and decrease their self-renewal capacity.[25] The inflammatory cytokines induced by general anesthetics may also impair neural progenitor cells proliferation and alter their differentiation.[26] These changes could adversely result in late cognitive dysfunction after general anesthesia in age-dependent manner.[27]

Dendritic development

The dendritic spines are the postsynaptic sites of most excitatory axodendritic synapses in the brain, and genesis of dendritic filopodia and spines formation play a critical role in synaptogenesis. Impairment of synaptogenesis potentially interferes with the development of neural networks. Recent studies from fixed brain preparations have shown that exposure to ketamine [28] and isoflurane decreases synapse or spine density in hippocampus of neonatal rodents. On the other hand, exposure to anesthetics midazolam, propofol, or ketamine causes a significant increase in the density of dendritic spines.[29] The effects of anesthetic exposure on synaptic connectivity in the brain may depend on developmental stage level [30] and the dose of anesthetics.[31] The mechanisms underlying the effects on anesthetics on synaptogenesis remain unclear, but at least may, in part, involve blockade of NMDA receptor activity or potentiation of GABAA receptor activity.

Neurite outgrowth

The effects of anesthetics on neurite outgrowth are reversible and transient.[32],[33] This makes anesthetics unlikely to induce cognitive dysfunction by this mechanism.

Glial development

Astrocytes, the most abundant glial cells in brain, are necessary for the formation, function, stability, and plasticity of synapses. Anesthetics may interfere at multiple levels to impair proper cytoskeletal development early, thereby disturbing glial growth and maturation.[34] The susceptibility of glial cells to anesthetic toxicity is age-dependent as well. The lethal anesthetic dose for immature glial cells and neural stem cells is greater than that for developing neurons.

[Figure 1] summarises the mechanisms of Anesthetic Induced Developmental Neurotoxicity
Figure 1: Summary of mechanisms of Anesthetic Induced Developmental Neurotoxicity

Click here to view



  Neurobehavior Mechanisms Top


Rapid brain development affects cognitive, social, and emotional growth during the first 3 years of a child's life. Experimental studies have shown that learning and memory are impaired in animals exposed to general anesthesia at early life based on results from neurocognitive tests. Most of these studies attribute this cognitive dysfunction to anesthetic-induced neuroapoptosis and impaired neurogenesis. However, human neurobehavior is undoubtedly complex such that subtle impairments in neurobehavior resulting from anesthesia are not easily detected through current neuropsychological and neurobehavior tests. Evidence has also indicated other sources of stress (surgical trauma, pain, etc.) during the perioperative period can increase the risk of stress-related neurocognitive problems well into the adult years.[35] It is difficult to evaluate the relationship between anesthesia and neurotoxicity in humans. It has been shown that anesthetic-induced neurotoxic effects can be compensated during growth and differentiation of the nervous system and that neurobehavior disorders can be restored in later life.[36] The mechanisms of neurobehavioral abnormalities induced by anesthetic exposure in early life need further investigation as the findings will have a profound implication on clinical practice.

Evidence from animal studies for neuronal toxicity of anesthetics

Studies demonstrated accelerated neuronal apoptosis in newborn rodents after they were exposed only to general anesthetics such as ketamine,[10] propofol,[37] nitrous oxide (N2O), sevoflurane, isoflurane,[38] desflurane, and benzodiazepines, without any other insults. In rats, the effect of anesthetics on apoptosis was greatest in 5–7 day olds. Furthermore, more prolonged exposure to anesthetics as well as exposure to multiple anesthetic agents in combination exacerbated the severity of the apoptosis. These findings cannot be translated to pediatric and obstetrics anesthesia practice for now, but they may provide insights into underlying mechanisms on neurotoxicity induced by anesthetics in the developing brain.

Factors influencing neuronal toxicity of anesthetics

Anesthetic exposure and timing

Exposure concentration and duration

Even lower volatile anesthetic concentration (for example, 0.5 minimum alveolar concentration) is usually used to protect against ischemic brain injury and can result in significant cytotoxicity subanesthetic concentration of halothane, sevoflurane, and desflurane (0.1%, 0.3%, and 0.6% in 3 L/min O2, respectively) which impair behavioral functions.[39] Alterations in learning and memory functions are greater with desflurane than with halothane and sevoflurane.[40] Desflurane but not isoflurane treatment induces almost no apoptosis or neurocognitive dysfunction.[41]

Difference between the two volatile anesthetics may be due to a difference in the effects of these anesthetics on mitochondrial function.[16],[42] Exposure to a combination of anesthetics (for example, N2O and desflurane) may cause more severe neuroapoptosis than to a single agent by itself.

Age dependency of apoptotic neurodegeneration

Developing brain more susceptible to anesthetic-induced neurotoxicity compared to the mature brain.[43] Anesthetics are more likely to cause adverse effects if the exposure interferes with the cascade of neurodevelopmental processes as during general anesthesia in pediatric or obstetric surgery.[44],[45],[46],[47] Anesthetic effects on the brain during its growth spurt period have led us to recognize that a developmental insult can initiate a cascade of alterations in neurodevelopment which can be detected structurally or functionally.

Human studies

There are several human cohort studies that suggest an association between early exposure to anesthetics and poor cognitive performance in later life.[8],[44],[46],[47],[48],[49],[50],[51] Those children receiving anesthesia before 3 years of age are more likely to have learning and behavior disorders compared with peers without anesthesia.[52],[53] Exposure to anesthesia in early life more than once or for a prolonged period adversely affects long-term neurodevelopmental outcomes in children.[44],[54] Based on these studies, it may be reasonable to speculate that neuropathological changes observed in the developing brain of animals similarly occur in brains of infants and children after anesthesia. However, coexisting conditions (low birth weight, medical problem, and especially surgical trauma) may preclude verification of the effect of anesthesia on cognitive development in human for ethical reasons. The currently available retrospective cohort studies in humans have some limitations to provide conclusive evidence. Since children in all of these studies had surgery, it is difficult to separate the effects of comorbidities, stress of surgery,[35] burden of illness (e.g., absenteeism from school) on learning, cognition, or behavior from anesthetic effects. Painful stimuli without analgesia and anesthesia have also been shown to initiate a harmful stress response in young children and to trigger neurotoxic effects in the developing brain, which can be blunted by anesthetics.[46] The ongoing studies may clarify a few of these issues. GAS study (A Multi-site Randomized Controlled Trial Comparing Regional and General Anesthesia for Effects on Neurodevelopmental Outcome and Apnea in Infants)[55] performed on infants requiring inguinal herniorrhaphy will attempt to separate the effects of general anesthesia from the surgical procedure. It was found no evidence that just <1 h of sevoflurane anesthesia in infancy increases the risk of adverse neurodevelopmental outcome at 2 years of age compared with awake-regional anesthesia.[56] Mayo Safety in Kids Study is a large cohort study long-term cognitive development of children with no anesthetic exposure to those with single or multiple exposures prior to age 3 years.[57] The presence of several social and environmental confounding factors and long lag time may also influence the results. Pediatric Anesthesia Neurodevelopmental Assessment Study has undergone a feasibility study [58] and is currently in the late planning stages. It compares a retrospective cohort of children who received anesthesia at <3 years of age with unanesthetized siblings in a prospective assessment of neurocognitive outcome in an attempt to reduce genetic and environmental contributions to cognitive performance.[58],[59]

The possibility of anesthetic-induced developmental neurotoxicity has potential implications for current anesthesia practice for pregnant women, infants, and children. Moreover, if it is finally concluded that anesthetic drugs do injure the developing brains, we would be confronted with the big question of what can be done about it? It is therefore essential to develop and explore clinically relevant neuroprotective strategies in animals that are likely to mitigate the neurotoxic effects of anesthetics.


  Methods of Protection Against Anesthetic-Induced Neurotoxicity – their Cellular and Molecular Mechanisms of Neuroprotection Top


The possibility of anesthetic-induced neurotoxicity raises concerns regarding current anesthesia practice for pregnant women, infants, and children. Accordingly, it is essential to develop and explore clinically relevant neuroprotective strategies in animals.

Erythropoietin

Erythropoietin (EPO) could have a direct neurotrophic and neuroprotective effect, particularly in conditions of neural damage Influence the release of neurotransmitters plays an important role in synaptic plasticity.[60] Anesthetics may inhibit EPO production, resulting in neurotoxicity.[61] Role of EPO needs to be established.

Brain preconditioning with anesthetics

Prior exposure to low dose of anesthesia, or a shorter duration of anesthetic exposure, can attenuate injury from high dose or prolonged anesthetic exposure in the developing brain.[62] Preconditioning with isoflurane,[63] propofol,[64] and ketamine can protect from anesthetic-induced neurotoxicity. Pretreatment with inertia gas anesthetic xenon can also attenuate anesthetic induced neurotoxicity.[65] Xenon's neuroprotective effect may be through its ability to inhibit intrinsic and common apoptotic pathways.[66] On the other hand, the anesthetic N2O or hypoxia pretreatment cannot protect from anesthetic-induced neuroapoptosis and cognitive function impairment.

Vitamins

Nicotinamide

Single dose of 1 mg/kg nicotinamide attenuates ketamine-induced neuronal cell loss in the developing rat brain. This reduced neuroapoptosis involves downregulation of Bax, inhibition of cytochrome c release from mitochondria into cytosol, and reduction in activated caspase-3 levels. Nicotinamide is also a potent inhibitor of pro-inflammatory cytokines. It may inhibit isoflurane-induced increase in levels of pro-inflammatory factors, tumor necrosis factor α, interleukin-6 (IL-6), and IL-1β, thus protecting from neurodevelopmental disorders.

Vitamin D3

Vitamin D3 (1-α-2,5-dihydroxy-Vitamin D3) can also protect against ketamine-induced neuroapoptosis. Vitamin D3 can induce CaBP expression or enhance trophic factor action, both of which can stabilize intracellular calcium.

Vitamin C, known as an antioxidant, may also be effective against anesthetic-induced neurotoxicity.

Alpha-2 adrenoceptor agonist

Alpha-2 (α2) adrenoceptor signaling plays a trophic role during neurodevelopment and is neuroprotective in several settings of neuronal injury. Dexmedetomidine neuroprotection appears to involve a decrease in cleaved caspase-3 levels and reversal of isoflurane-induced decrease in anti-apoptotic Bcl-1, pERK1, and pERK2 protein expression in vivo. Neuroprotective mechanisms of α2 adrenoceptor signaling also involve inhibition of calcium entry, scavenging of glutamate, and reduction in NMDA receptor activation.

Lithium

Lithium, as a glycogen synthase kinase-3β inhibitor, has shown protective effects against neuroapoptosis induced by drugs. Lithium treatment can also significantly increase BDNF serum levels and suppress neuroapoptosis in the central nervous system through the BDNF-Akt-Bcl-2 antiapoptotic signaling pathway.

Injection of Activity-dependent neuroprotective proteincan inhibit anesthetic-induced caspase levels in a dose-dependent manner.

Melatonin

Neuroprotective effect may be mediated by inhibition of mitochondria-dependent apoptotic pathway.

Acetyl-L-carnitine

It metabolized in the brain to acetyl coenzyme A which subsequently enters the tricarboxylic acid cycle. It has been found to effectively block neuronal apoptosis caused by exposure to a combination of N2O and isoflurane.


  Conclusion Top


These effects occur at very specific stages of development and are dose-dependent. Human research evaluating the long-term effects of anesthesia on brain development is limited and to date has been limited to retrospective observational cohort studies. The results of these studies have not been consistent, with some demonstrating an association between surgery and adverse neurobehavioral outcome and others showing no association. At this stage, it is impossible to definitively know whether early exposure to anesthesia holds any clinically relevant long-term risk for the brain.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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