Journal of Neuroscience and Neuropharmacology

Recent Advances and Emerging Problems in Developmental Neurotoxicology

Keith Herbert^{* *}Correspondence: Keith Herbert, Department of Neuropharmacology, Belgium, Email:

Author info »

Introduction

A growing body of research has shown that general anaesthetics have the potential to cause developmental neurotoxicity, including abrupt, widespread neuronal cell death, followed by impairments in learning and long-term memory. Induction and maintenance of anaesthesia, as well as procedural and critical care sedation in children, are all often achieved with the intravenous anaesthetic drug propofol. There isn't as much data available about its possible role in neurotoxicity as there is for other anaesthetic medications. Propofol's neurotoxic effects have been linked to other anaesthetic medicines, according to mounting data from several animal models, which has led to major concerns about the use of propofol in paediatric anaesthesia. The objective of this review is to provide a concise summary of the most recent research on the developmental neurotoxicity caused by protocol. We begin by outlining the proof of neurotoxicity obtained from investigations using human stem cell-derived neurons as well as animal models, animal cell culture and animal cell culture. The mechanism of protocol-induced developmental neurotoxicity is then covered, including higher rates of cell death in neurons and oligodendrocytes, aberrant dendritic formation, dysregulated neurogenesis, and decreased expression of neurotrophic factors. We also highlight recent research on intricate mechanisms of propofol action, including changes in mRNAs and mitochondrial fission.

Understanding the neurotoxicity of propofol and the underlying processes may aid in the development of efficient new preventative or therapeutic measures to lessen its effects on the growing human brain.

Numerous neuropsychiatric disorders, ranging from mental retardation to schizophrenia, are thought to be caused by a mix of hereditary and environmental factors, with the latter having an impact on the developing brain at key times. We have been investigating the processes through which environmental variables might impair brain development, leading to neurobehavioral disorders that may manifest in childhood or with delayed onset in adulthood. The revelation that Glutamate (Glu), a common dietary ingredient, kills neurons in the developing brain thirty years ago provided a significant incentive for this field of study. It was discovered that giving Glu orally or subcutaneously to young animals—mice, rats, rabbits, guinea pigs, and monkeys at dosages that don't seem to hurt or interfere with their usual behavior quietly kills a significant number of neurons in the developing hypothalamus. During infancy, there were no overt symptoms of dysfunction caused by this pathological event; however, as the animals grew to adolescence, they developed an abnormal body habitus (short and fat), and they were found to have some neuroendocrine abnormalities, including hypogonadism, infertility, and a smaller pituitary gland.

We hypothesized that additional pathways could also be capable of causing quite harm to the growing brain, harm that might not manifest as a functional defect until later in ontogenesis when the damaged brain circuitry fails to form and take on its adult roles.

There is less information known on propofol neurotoxicity than there is for other anaesthetic medicines. It is quite lipophilic, propofol. Beginning in 1989, propofol was used intravenously to induce and maintain drowsiness throughout therapy. Neither the maintenance of the anaesthetic nor the patients' recovery from it was associated with any life-threatening consequences. Additionally, compared to other anaesthetics, propofol had fewer adverse effects. Due to its quick onset and fast washout after the accompanying medical operation, propofol has now become frequently employed. Propofol is an incredibly helpful drug for producing and sustaining general anaesthesia due to its highly quick loss of consciousness following a single dosage and rapid recovery after cessation of treatment. One of the most frequently used intravenous medicines for inducing and maintaining general anaesthesia is propofol, which is utilized in more than 50 nations and more than 75% of operations.

Today, one in every six kids is diagnosed with a developmental problem, and the Central Nervous System (CNS) is frequently involved. 10% to 15% of all babies have neurobehavioral development disorders. There are several common neurodevelopmental problems, such as Attention Deficit and Hyperactivity Disorder (ADHD), autism spectrum disorders, and learning disabilities. ASD affects 1 in 110 people in the US, rising to 1 in 68 according to the CDC in 20142, and affects people aged 1 to 64 age in the UK. ADHD affects 14% of the 4 million children born in the US each year while learning difficulties can impact up to 10% of students in public schools. Scientific data shows that the frequency of these illnesses is rising, even though the assessment and reporting of these problems have improved over the past several years. Recent research has shown that propofol can cause developmental neurotoxicity in a variety of settings (such as animal models and cell culture systems), which has led to severe concerns about the safety of paediatric propofol anaesthesia. Nowadays, most situations require exposing children to anaesthetics, thanks to medical advancements. However, there is a need to give the potential that the neurotoxicity caused by propofol that has been seen in animal models might also be relevant to humans serious thought. In recent years, there have been an increasing number of studies attempting to develop a stem cell model to examine the toxic effect of general anaesthetics on human neurons and demonstrate the toxic effect of these potent drugs. This is because it is also impossible to obtain direct histological evidence of anaesthetic neurotoxicity in young patients and their derived neural cell lineages.

Particularly susceptible to toxic harm is the growing neurological system. Neurobehavioural changes that can occur after chemical exposure have been utilized as sensitive readouts to gauge neurotoxicity in both animals and people. Determining specific neurotoxic effects in cell-based systems may be made possible by breaking down neurobehavior into pertinent cellular and molecular components. This may make it simpler to examine the neurotoxic pathways and modes of action and, ultimately, to inform the regulatory assessment of chemicals that may be neurotoxic to development. Here, progress made in achieving these goals is examined. Neurobiological correlates of cognitive function are being utilized to define neurotoxic processes, and imaging genetics offers novel insights into these correlates. Studies of synaptic plasticity taken ex vivo help to close the gap between in vivo neurobehavioral data and real-time in vitro measurements of neuronal function. The N-Methyl-D-Aspartate (NMDA)-glutamate receptor is a typical target for solvent neurotoxicity, and it can relate an in vivo neurological impairment to in vitro readouts. In vitro tests on animals exposed to polychlorinated biphenyls and organophosphorus pesticides showed that axonal and dendritic morphology were reliable predictors of neural connection and neurobehavior. The development of neural networks on structured surfaces was also influenced by chemically induced alterations in neuronal morphology.