A pinboard by
Atul Malhotra

PhD student, Monash University


Healthy start to life

I am a clinician who looks after sick newborn infants. Many of them are at risk of lung and brain injury at the start of life as they are very vulnerable soon after they are born. This puts them at risk of possible life long debilitating illnesses and disabilities. Currently, no definitive therapy is available to prevent or treat this lung or brain injury. This drove me to "Science" for questions and possible solutions. My PhD focuses on why some babies are at high risk of brain injury in the newborn period, what are the mechanisms involved, how we can detect this brain injury earlier, and to test novel therapies to prevent and treat this brain injury. I work in the pre-clinical space with animal research. We have animal models for the specific conditions which affect the human babies, and this gives us an opportunity to comprehensively study the effects of high risk conditions on the brains of these animals. Through my research, I have studied the mechanisms likely to be involved in the development of brain injury in newborn babies, i understand them better now. This is being published very shortly. I have also worked on better techniques to recognize this brain injury using novel tools. Most exciting of all, is that we are evaluating the benefits of novel therapies (Stem cells) on brain injury in these high risk though relatively common conditions. This is even more exciting as i have recently finished a pilot trial of using stem cells in another condition of sick newborn infants, lung disease. I want to present the therapeutic arm of the findings of my research to this prestigious conference next year. The results of this are exciting, as they set the scene for more research in the area using stem cells. Like, one of the mothers of the lung trial recently said, "It is a miracle my baby is so much better now after treatment with stem cells and will have a great life ahead". This is what drives my research - A Healthy start to Life!


The sigma-1 receptor agonist 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) protects against newborn excitotoxic brain injury by stabilizing the mitochondrial membrane potential in vitro and inhibiting microglial activation in vivo.

Abstract: Premature birth represents a clinical situation of risk for brain injury. The diversity of pathophysiological processes complicates efforts to find effective therapeutic strategies. Excitotoxicity is one important factor in the pathogenesis of preterm brain injury. The observation that sigma-1 receptor agonists possess neuroprotective potential, at least partly mediated by a variety of anti-excitotoxic mechanisms, has generated great interest in targeting those receptors to counteract brain injury. The objective of this study was to evaluate the effect of the highly specific sigma-1 receptor agonist, 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) to protect against excitotoxic developmental brain injury in vivo and in vitro. Primary hippocampal neurons were pre-treated with PPBP before glutamate was applied and subsequently analyzed for cell death (PI/calcein AM), mitochondrial activity (TMRM) and morphology of the neuronal network (WGA) using confocal microscopy. Using an established neonatal mouse model we also determined whether systemic injection of PPBP significantly attenuates excitotoxic brain injury. PPBP significantly reduced neuronal cell death in primary hippocampal neurons exposed to glutamate. Neurons treated with PPBP showed a less pronounced loss of mitochondrial membrane potential and fewer morphological changes after glutamate exposure. A single intraperitoneal injection of PPBP given one hour after the excitotoxic insult significantly reduced microglial cell activation and lesion size in cortical gray and white matter. The present study provides strong support for the consideration of sigma-1 receptor agonists as a candidate therapy for the reduction of neonatal excitotoxic brain lesions and might offer a novel target to counteract developmental brain injury.

Pub.: 12 Aug '14, Pinned: 25 Aug '17

Stem cell therapy to protect and repair the developing brain: a review of mechanisms of action of cord blood and amnion epithelial derived cells.

Abstract: In the research, clinical, and wider community there is great interest in the use of stem cells to reduce the progression, or indeed repair brain injury. Perinatal brain injury may result from acute or chronic insults sustained during fetal development, during the process of birth, or in the newborn period. The most readily identifiable outcome of perinatal brain injury is cerebral palsy, however, this is just one consequence in a spectrum of mild to severe neurological deficits. As we review, there are now clinical trials taking place worldwide targeting cerebral palsy with stem cell therapies. It will likely be many years before strong evidence-based results emerge from these trials. With such trials underway, it is both appropriate and timely to address the physiological basis for the efficacy of stem-like cells in preventing damage to, or regenerating, the newborn brain. Appropriate experimental animal models are best placed to deliver this information. Cell availability, the potential for immunological rejection, ethical, and logistical considerations, together with the propensity for native cells to form teratomas, make it unlikely that embryonic or fetal stem cells will be practical. Fortunately, these issues do not pertain to the use of human amnion epithelial cells (hAECs), or umbilical cord blood (UCB) stem cells that are readily and economically obtained from the placenta and umbilical cord discarded at birth. These cells have the potential for transplantation to the newborn where brain injury is diagnosed or even suspected. We will explore the novel characteristics of hAECs and undifferentiated UCB cells, as well as UCB-derived endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs), and how immunomodulation and anti-inflammatory properties are principal mechanisms of action that are common to these cells, and which in turn may ameliorate the cerebral hypoxia and inflammation that are final pathways in the pathogenesis of perinatal brain injury.

Pub.: 30 Oct '13, Pinned: 25 Aug '17

New imaging approaches to evaluate newborn brain injury and their role in predicting developmental disorders.

Abstract: This review highlights recent work using advanced imaging approaches that have improved our understanding of the underlying neural mechanisms associated with disrupted brain development or demonstrated the potential of MRI to provide objective biomarkers of cerebral injury that relate to subsequent neurodevelopmental performance.Preterm birth impacts on the development of thalamocortical connections to inferior frontal and medial temporal cortex, and cingulate gyri. Impairments to cortical development in these regions are evident in early adulthood and associated with lower intelligence quotient scores. Disruptions to microstructural development of cortical gray matter are prevalent in survivors of preterm birth and related to immaturity at birth, postnatal growth and neurodevelopmental performance. Brain dysmaturation is also evident in infants with congenital heart disease and is detectable prior to surgery, highlighting the influence of adverse conditions on in-utero brain development. In infants with hypoxic-ischemic encephalopathy who have undergone therapeutic hypothermia, quantitative magnetic resonance measures in the neonatal period are related to performance at 2 years.Advanced MRI approaches offer the opportunity to assess objectively brain structure and function, and a number of studies, spanning different patient groups, demonstrate their utility as early biomarkers of altered neurological outcome.

Pub.: 25 Feb '14, Pinned: 25 Aug '17