Neurotoxic Treatments in the Newborn Period
Mustafa
Aydin, Ugur Deveci, Aysen Orman
Mustafa Aydin, Ugur
Deveci, Aysen Orman, Department
of Pediatrics-Neonatology, Firat University School of Medicine, Elazig, Turkey
Correspondence to: Mustafa Aydin, MD, Department of
Pediatrics-Neonatology, Firat University School of Medicine, 23119, Elazig,
Turkey
Email: dr1mustafa@hotmail.com
Telephone: +90-424-2333555
Fax:
+90-424-2388096
Received: March 29,
2015
Revised: May 14, 2015
Accepted: May 18, 2015
Published online: September 1, 2015
ABSTRACT
The
neurotoxic substances might cause damage to neuronal tissue by altering the
normal activity of the nervous system which could eventually disrupt or even
kill the neurons. Fetal and neonatal life is very sensitive period because of
the active brain development that could be easily affected by endogenous or
exogenous factors. Many pregnant women and newborn infants receive some
treatments because of their clinical conditions which may impair or disrupt the
developing brain of the newborn. Therefore, clinicians should be aware of
potential adverse effects of the certain medications which may cause permanent
long term sequela.
© 2015 ACT. All
rights reserved.
Key words: Brain; Drugs; Glutamate; N-methyl-D-aspartate receptors;
Fetus; Newborn infant; Neurotoxicity; Neurodevelopment
Aydin M, Deveci U,
Orman A. Neurotoxic Treatments in the Newborn Period. International
Journal of Neurology Research 2015; 1(3): 153-157 Available from: URL:
http://www.ghrnet.org/index.php/ijnr/article/view/1139
REVIEW
Neurotoxicity is defined as the alteration of the normal nervous system
activity in an unfavorable manner by endogenous or exogenous substances. Examples
of such endogenous molecules include glutamate, bilirubin, nitric oxide,
histamine, while alcohol or carbon monoxide represents exogenous insults. Such
alterations in the neurons are sometimes not limited to functions, but also
involve the anatomy, i.e. the cell structure, of the neurons. The term
neuronopathy refers to the death (necrosis or apoptosis) of the neuronal
cell, and a dead neuron cannot be replaced by new neurons. Types of
neurotoxicity other than neuronopathy include axonopathy, myelinopathy, or
blockade of the neurotransmission. The duration and intensity of exposure to
neurotoxic insult has a significant role on the outcome of the toxic effect.
Most of the neurotoxins act by impairing the voltage-dependent ion channels
(sodium, potassium, and calcium channels)[1,2].
During the
quick brain development phase in newborns, susceptibility of the immature brain
to the noxious effects of neurotoxic agents is more marked due to the presence
of significant synaptogenic activity. Experimental studies in animals have
shown that general anesthetic agents may be potentially toxic for the
developing brain. Exposure to anesthetic agents may cause neurodegeneration
through induction of apoptosis and impaired neurogenesis at a critical stage of
neurodevelopment, potentially leading to a significant impact on the
neurocognitive functions in later life[3-7]. Therefore,
neurotoxicity should be considered as a significant potential drug-related side
effect in susceptible populations, such as premature infants and pregnant
women.
Despite their
role in neuronal tissue physiology and synaptic plasticity,
N-methyl-D-aspartate (NMDA)-type glutamate receptors, under certain
circumstances, may be associated with acute or chronic neurotoxic effects
(Figure 1)[8]. In a multitude of neuropathological conditions, NMDA
receptors are the foremost mediators of neuronal cell death. Investigational
data suggest that in addition to NMDA receptor antagonists, agents with a
stimulatory effect on gamma-aminobutyric acid signal transduction may also
exert potentially neurotoxic effects on the developing brain. Animal studies
have established the role of NMDA receptors in the neurotoxic effects of
general anesthetic agents commonly utilized in the clinical practice[3,9-11].
Ketamine, an NMDA receptor
antagonist, is a widely used general anesthetic agent in procedures involving
pediatric patients. However, significant concerns have been raised in terms of
the safety of ketamine in pediatric anesthesia. Repeated doses of ketamine have
resulted in permanent learning and memory disorders through the induction of
neuroapoptosis and injury in the developing brain, mainly at the hippocampal
area in animal studies. On the other hand, the exact mechanism of ketamine
related neurotoxicity is not very well known. The major factor responsible for
ketamine neurotoxicity is the reactive oxygen species-mediated neuronal
apoptosis occurring via the mitochondrial pathways. Up-regulation of NMDA
receptors lead to toxic levels of intracellular calcium accumulation, thus
resulting in neurotoxicity. Although experimental work has suggested that
certain antioxidant agents such as L-carnitine may partly alleviate this
injury, novel strategies that may help prevent injury are warranted (Figures 2-4)[12-15].
Otherwise, in a study conducted by Tariq et al[16] it is
demonstrated that chronic administration of the dexmedetomidine, a highly
selective and specific alpha-2 adrenergic agonist with sedative, analgesic and
sympathetic activities, significantly reduced the body weight and crown-rump
length of pups, whereas a single acute dose did not affect these parameters.
Local
anesthetics are used clinically for peripheral nerve blocks, epidural
anesthesia, spinal anesthesia and pain management; large concentrations,
continuous application and long exposure time can cause neurotoxicity. The
mechanism of neurotoxicity caused by local anesthetics is unclear. Neurite
outgrowth and apoptosis can be used to evaluate neurotoxic effects. Many
previous studies have been reported neurological injury caused by local
anesthetics. Lidocaine, a local anesthetic, may also be used systemically for
an antiarrhythmic effect in certain dysrhythmias and for an anticonvulsant
effect in refractory convulsions. Its higher plasma concentrations may cause
seizure activity (proconvulsant effect). In addition, neurotoxic effect of
lidocaine in the newborn period has also been reported[17,18]. In a
study, local anesthetics had produced toxic effects by neurite inhibition at
low concentrations and by apoptosis at high concentrations[17].
Other agents
with demonstrated neurotoxic effects include some sedatives and analgesic
agents. For instance, chloral hydrate has been found to be associated with
lower performance intelligence quotient (PIQ) and cumulative doses of
benzodiazepines were associated with lower visual motor integration (VMI).
Chloral hydrate is commonly used as a sedative and a hypnotic in pediatric
medicine. It has the embryotoxic effects and an increase in the number of
malformed offspring. Midazolam is known to increase the convulsion frequency in
premature infants and in patients with a lower threshold for convulsions.
Again, serious concerns have been expressed regarding the safety of
phenobarbital, in terms of its potential role in the development of
hyperactivity, behavioral problems, and even dementia. Phenobarbital exposure
at the critical stages of brain development has adverse consequences with
regard to the functions of the nervous system. Exposure to phenobarbital at
earlier stages of life leads to neuronal apoptosis and impairs the
physiological maturation of the neuronal synapses. Similarly, barbiturate
exposure has been linked to the development of autism[19-21].
In prenatal
alcohol exposure, particularly in cases with fetal alcohol syndrome,
psychosocial adaptation problems in later stages of life are more likely to be
observed. Long-term use of psychostimulant agents, like morphine, lead to some
pathological consequences including neurotoxicity and neuronal dysfunction,
hepatotoxicity, kidney dysfunction by causing injury on biomolecules through
oxidative stress and apoptosis. Amphetamine-like psychostimulant agents are
commonly used for their potent stimulatory effects on the central nervous system,
and have been associated with long-term neuro-toxicity as well as related
behavioral problems[22-24].
Intrauterine
exposure to antidepressants is also associated with some short- or long-term
risks. Antenatal exposure to selective serotonin re-uptake inhibitors (SSRI)
may lead to serotonin toxicity and withdrawal symptoms in the short term, while
latent functional behavioral disorders have been reported in the long term[25,26].
For instance, in a study involving pediatric subjects, assessments based on The
Bayley Scales of Infant and Toddler Development, Third Edition showed lower
motor scores, mainly in fine motor skills of the participants[27].
In addition, exposure to SSRI during the third trimester of the pregnancy was
associated with a poorer motor development, lower APGAR score, a method to
quickly evaluate the health of newborn infants after birth which summarized
using words chosen to form a backronym (Appearance, Pulse, Grimace, Activity,
Respiration), at 5 minutes, and shorter gestational age[28].
Considering the important role of serotonin in central nervous system
development, more studies are needed to assess the possible adverse effects on
long-term neurodevelopment. Thus, SSRIs should only be used when the benefits
clearly outweigh the risks during pregnancy and those children with a history
of exposure to SSRI use during pregnancy should be closely monitored for
potential adverse effects.
Fetal exposure
of animals to antiepileptic drugs can produce cognitive and behavioral
abnormalities, but cognitive effects of fetal exposure of humans to
antiepileptic drugs are uncertain. Accumulating evidence suggests an
association between prenatal exposure to antiepileptic drugs and increased risk
of both physical anomalies and neurodevelopmental impairment.
Neurodevelopmental impairments are characterized by either a specific deficit
or a constellation of deficits across cognitive, motor and social skills and
can be transient or continuous into adulthood. Exposure to certain
antiepileptic drugs during the early stages of life also constitutes the risk
factor for neuropsychiatric abnormalities, as exemplified by studies that show
that antenatal exposure to valproic acid was associated with lower IQ, which is
sufficient to affect education and occupational outcomes in later life; and
antenatal exposure to carbamazepine was associated with lower developmental
quotient (DQ)[29]. In a study, it is demonstrated that in utero
exposure to valproate, as compared with other commonly used antiepileptic drugs,
was associated with an increased risk of impaired cognitive function at 3 years
of age[30]. Therefore, it is of paramount importance that these
potential risks are taken into account or minimized in these vulnerable
populations.
Theophylline,
a metylxhantine derivative commonly used during the newborn period for apnea of
prematurity, may also induce apoptosis, and corticosteroids, particularly
dexamethasone, are known to induce similar effects such as neurodevelopmental
retardation and cerebral palsy in the long term. In an experimental study,
theophylline was found to induce convulsive activity through free radicals
(reactive oxygen species and reactive nitrogen species). In animals,
aminophylline was shown to increase hippocampal neuronal cell injury[31,32].
But there is conflicting data for caffeine; even it may have neuroprotective
effects[33]. Therefore, additional randomized trials are needed to
determine possible long-term neurologic benefits of caffeine. Again, in animals,
corticosteroids were associated with neurodevelopmental problems, with a
particularly marked adverse effect on neuronal cell division and myelination in
the first days of life, which are critical for brain development[34-38].
However, in an experimental study, hydrocortisone has been demonstrated safer
than dexamethasone in the immediate postnatal period in neonatal rats[39].
Antibacterial
agents may also be related to a variety of neurotoxic reactions, such as direct
neurotoxicity (e.g. penicillin, cephalosporin, imipenem, colistin,
metronidazole), cranial nerve toxicity (e.g. vancomycine, aminoglycosides) or
neuromuscular blockade (e.g. clindamycin, aminoglycosides). For example,
cefepime related non-convulsive status epilepticus have been reported in adults
as well as clarithromycin associated neuropsychotic disorders, and convulsions
in those with a low threshold for epileptic activity[40-42].
Other known
neurological side effects due to drugs administered to newborns include apnea
and convulsions due to prostaglandin E1 infusion for duct-dependent congenital
heart disease, dystonic reactions due to metoclopramide for gastroesophageal
reflux disease, and elevated intracranial pressure due to high dose vitamin A[43-45].
Vitamin A toxicity is a good model of vitamin neurotoxicity, because it shows
the importance of the vitamin and vitamin-binding proteins ratio to causes
vitamin toxicity and passes over to central nervous system barriers. Folic acid
and thiamine cause seizures and excitation when administered in high dosage
directly into the brain or cerebrospinal fluid of experimental animals but have
rarely been reported to cause neurotoxicity in human. Ascorbic acid influences
brain cell differentiation and 2-deoxyglucose accumulation by cultured glial
cells after peripheral administration. Biotin also influences gene expression
in animals and alters astrocyte glucose utilization[46].
In conclusion,
since the antenatal and neonatal periods are very sensitive periods with rapid
brain development occurring, the fetuses and newborn infants might exposure to
potentially neurotoxic side effects of commonly used many drugs. Therefore,
potential neurotoxic side effects of commonly used drugs in the both pregnant
women and newborns, especially in preterm infants, should be taken into
account; and therefore, before starting a treatment to these vulnerable
populations, the necessity and benefit to harm ratio should be questioned.
CONFLICT OF INTERESTS
The authors have no conflicts of interest to declare.
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Peer reviewers: Yanguo
Hong, Professor, Dept. of Physiology, College of Life Sciences, Fujian Normal
University, University town, Fuzhou, Fujian Province, 350108, China; Somayeh
Hosseinzadeh , Babol University of Medical Sciences, Babol, Iran, Faculty of
Physical Education and Exercise Sciences, University of Mazandaran, Babolsar,
Iran; Haseeb Ahmad Khan, Distinguished Professor, Department of Biochemistry,
College of Science, Bldg. 5, King Saud University, P.O. Box 2455, Riyadh 11451,
Saudi Arabia.
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