Norman Ruthven Saunders

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• BSc (Hons) MBBS PhD
• Adjunct Professor at Monash University (Australia)

Background The integrity of blood–brain and blood-cerebrospinal fluid (CSF) barriers is characterised by their ability to restrict transcellular passage of inert, hydrophilic markers of different molecular sizes by tight junctions between barrier forming cells. Compromised barrier integrity has been linked to many pathologies, including epilepsy....

Valproate is an antiseizure drug required by many epileptic patients to manage their symptoms. During pregnancy, its use has been shown to increase the risk of neurobehavioral deficits in the offspring. The present study used a rat model of absence epilepsy, Genetic Absence Epilepsy Rat from Strasbourg (GAERS), to investigate the effects of gestati...

Background Due to its availability and perceived safety, paracetamol is recommended even during pregnancy and for neonates. It is used frequently alone or in combination with other drugs required for the treatment of various chronic conditions. The aim of this study was to investigate potential effects of drug interactions on paracetamol metabolism...

Background The aim of this study was to explore whether sail training using a VSail® simulator would allow people with spinal cord injuries (SCI) to learn to sail in a safe controlled environment and then sail competently on the water in wind of moderate strength (12 knots). A battery of physical tests and questionnaires was used to evaluate possib...

Background: Paracetamol is one of the most commonly used medications. Due to its availability and perceived safety, its use is recommended even during pregnancy and for neonates. It is often combined with other drugs required for various chronic treatments. However, potential effects of drug interactions on paracetamol brain entry, especially in ea...

During development, embryos and foetuses may be exposed to maternally ingested antiseizure medications (ASM), valproate and lamotrigine, essential in some patients to control their epilepsy symptoms. Often, the two drugs are co‐administered to reduce required doses of valproate, a known potential teratogen. This study used Genetic Absence Epilepsy...

This study used a marsupial Monodelphis domestica , which is born very immature and most of its development is postnatal without placental protection. RNA‐sequencing (RNA‐Seq) was used to identify the expression of influx and efflux transporters (ATP‐binding cassettes [ABCs] and solute carriers [SLCs]) and metabolizing enzymes in brains of newborn...

Cannabidiol is a major component of cannabis but without known psychoactive properties. A wide range of properties have been attributed to it, such as anti-inflammatory, analgesic, anti-cancer, anti-seizure and anxiolytic. However, being a fairly new compound in its purified form, little is known about cannabidiol brain entry, especially during dev...

Background The aim of this study was to explore whether sail training using a VSail® simulator would allow people with spinal cord injuries (SCI) to learn to sail in a safe controlled environment and then sail competently on the water in wind of moderate strength (12 knots). A battery of physical tests and questionnaires was used to evaluate possib...

Solute carriers (SLCs) regulate transfer of a wide range of molecules across cell membranes using facilitative or secondary active transport. In pregnancy, these transporters, expressed at the placental barrier, are important for delivery of nutrients to the fetus, whilst also limiting entry of potentially harmful substances, such as drugs. In the...

Cannabidiol is a major component of cannabis but without known psychoactive properties. A wide range of properties have been attributed to it, such as anti-inflammatory, analgesic, anti-cancer, anti-seizure and anxiolytic. However, being a fairly new compound in its purified form, little is known about cannabidiol brain entry, especially during dev...

Solute carriers (SLCs) regulate transfer of a wide range of molecules across cell membranes using facilitative or secondary active transport. In pregnancy, these transporters, expressed at the placental barrier, are important for delivery of nutrients to the developing fetus, whilst also limiting entry of potentially harmful substances such as drug...

Background: Olanzapine is used to treat schizophrenia and bipolar disorder in women of childbearing age. Continuation of psychotropic medications throughout pregnancy and lactation is often required as cessation could be dangerous for both mother and child. However, there is a lack of information on the transfer of these drugs into the developing b...

Binding of therapeutics to proteins in blood plasma is important in influencing their distribution as it is their free (unbound) form that is able to cross cellular membranes to enter tissues and exert their actions. The concentration and composition of plasma proteins vary during pregnancy and development, resulting in potential changes to drug pr...

Background: Olanzapine is used to treat schizophrenia and bipolar disorder in women of childbearing age. Continuation of psychotropic medications throughout pregnancy and lactation is often required as cessation could be dangerous for both mother and child. However, there is a lack of information on the transfer of these drugs into the developing b...

Background Apparent permeability of the blood brain barrier to hydrophilic markers has been shown to be higher in the developing brain. Apart from synthesis in situ, any substance detected in the brain parenchyma can originate from two sources: directly through blood vessels of brain vasculature and/or indirectly by entry from the cerebrospinal flu...

Studies of the choroid plexuses lag behind those of, the more widely known, blood brain barrier in spite of a much longer history. This review has two overall aims. The first is to outline longstanding areas of research where there are unanswered questions, such as control of cerebrospinal fluid (CSF) secretion and blood flow. The second part revie...

Background Permeability of blood brain barrier to hydrophilic markers has been shown to be higher in the developing brain. Apart from synthesis in situ, any substance detected in the brain parenchyma can originate from two sources: directly through blood vessels of brain vasculature and/or indirectly by entry from the cerebrospinal fluid (CSF) afte...

Background Little is known about the extent of drug entry into developing brain, when administered to pregnant and lactating women. Lithium is commonly prescribed for bipolar disorder. Here we studied transfer of lithium given to dams, into blood, brain and cerebrospinal fluid (CSF) in embryonic and postnatal animals as well as adults. Methods Lit...

Adenosine triphosphate binding cassette (ABC) transporters transfer lipid-soluble molecules across cellular interfaces either directly or after enzymatic metabolism. RNAseq analysis identified transcripts for ABC transporters and enzymes in rat E19, P5 and adult brain and choroid plexus and E19 placenta. Their functional capacity to efflux small mo...

Background: Women with epilepsy face difficult choices whether to continue antiepileptic drug treatment during pregnancy, as uncontrolled seizures carry great risk to mother and fetus but continuing treatment may have adverse effects on baby’s development. This study aimed at evaluating antiepileptic drug entry into developing brain. Methods: Anaes...

Adenosine triphosphate binding cassette (ABC) transporters transfer lipid-soluble molecules across cellular interfaces either directly or after enzymatic metabolism. RNAseq analysis identified transcripts for ABC transporters and enzymes in rat E19, P5 and adult brain and choroid plexus and E19 placenta. Their functional capacity to efflux small mo...

Background: Women with epilepsy face difficult choices whether to continue antiepileptic drug treatment during pregnancy, as uncontrolled seizures carry great risk to mother and fetus but continuing treatment may have adverse effects on baby’s development. This study aimed at evaluating antiepileptic drug entry into developing brain. Methods: Anaes...

Abstract Background Adenosine triphosphate binding cassette transporters such as P-glycoprotein (PGP) play an important role in drug pharmacokinetics by actively effluxing their substrates at barrier interfaces, including the blood-brain, blood-cerebrospinal fluid (CSF) and placental barriers. For a molecule to access the brain during fetal stages...

Background: Adenosine triphosphate binding cassette transporters such as P-glycoprotein (PGP) play an important role in drug pharmacokinetics by actively effluxing their substrates at barrier interfaces, including the blood-brain, blood-cerebrospinal fluid (CSF) and placental barriers. For a molecule to access the brain during fetal stages it must...

Background Little is known about the extent of drugs administered to pregnant and lactating women entering the developing brain. Lithium is one of the most commonly prescribed drugs for bipolar disorder. Here we studied transfer of lithium given to dams, into blood, brain and cerebrospinal fluid (CSF) in embryonic, postnatal and adult rats. Methods...

Background Little is known about the extent of drug entry into developing brain, when administered to pregnant and lactating women. Lithium is commonly prescribed for bipolar disorder. Here we studied transfer of lithium given to dams, into blood, brain and cerebrospinal fluid (CSF) in embryonic and postnatal animals as well as adults. Methods Lith...

Background: Paracetamol (acetaminophen) is widely used in pregnancy and generally regarded as “safe” by regulatory authorities. Methods: Clinically relevant doses of paracetamol were administered intraperitoneally to pregnant rats twice daily from embryonic day E15 to 19 (chronic) or as a single dose at E19 (acute). Control samples were from un-tre...

Background: Paracetamol (acetaminophen) is widely used in pregnancy and generally regarded as “safe” by regulatory authorities. Methods: Clinically relevant doses of paracetamol were administered intraperitoneally to pregnant rats twice daily from embryonic day E15 to 19 (chronic) or as a single dose at E19 (acute). Control samples were from un-tre...

Drug entry into the adult brain is controlled by efflux mechanisms situated in various brain barrier interfaces. The effectiveness of these protective mechanisms in the embryo, fetus and newborn brain is less clear. The longstanding belief that “the” blood brain barrier is absent or immature in the fetus and newborn has led to many misleading state...

Background: A major concern for clinicians in prescribing medications to pregnant women and neonates is the possibility that drugs might have damaging effects, particularly on long-term brain development. Current understanding of drug permeability at placental and blood-brain barriers during development is poor. In adults, ABC transporters limit ma...

Many pregnant women and prematurely born infants require medication for clinical conditions including cancer, cardiac defects and psychiatric disorders. In adults drug transfer from blood into brain is mostly restricted by efflux mechanisms (ATP-binding cassette, ABC transporters). These mechanisms have been little studied during brain development....

Efflux mechanisms situated in various brain barrier interfaces control drug entry into the adult brain; this review considers the effectiveness of these protective mechanisms in the embryo, fetus, and newborn brain. The long-standing belief that the blood-brain barrier is absent or immature in the fetus and newborn has led to many misleading statem...

Background: After a short gestation, marsupials give birth to immature neonates with lungs that are not fully developed and in early life the neonate partially relies on gas exchange through the skin. Therefore, significant lung development occurs after birth in marsupials in contrast to eutherian mammals such as humans and mice where lung develop...

Properties of the local internal environment of the adult brain are tightly controlled providing a stable milieu essential for its normal function. The mechanisms involved in this complex control are structural, molecular and physiological (influx and efflux transporters) frequently referred to as the “blood‐brain barrier”. These mechanisms include...

Adult brain is protected from entry of drugs and toxins by specific mechanisms such as ABC (ATP-binding Cassette) efflux transporters. Little is known when these appear in human brain during development. Cellular distribution of three main ABC transporters (ABCC1, ABCG2, ABCB1) was determined at blood-brain barriers and interfaces in human embryos...

There is considerable debate about whether the partition volumes of the mammalian brain (e.g. cerebrum, cerebellum) evolve according to functional selection, or whether developmental constraints of conserved neurogenetic scheduling cause predictable partition scaling with brain size. Here we provide the first investigation of developmental constrai...

Background: Most animal studies of spinal cord injury are conducted in quadrupeds, usually rodents. It is unclear to what extent functional results from such studies can be translated to bipedal species such as humans because bipedal and quadrupedal locomotion involve very different patterns of spinal control of muscle coordination. Bipedalism requ...

There are five exchange interfaces between the peripheral circulation (blood), the cerebrospinal fluid (CSF) and the brain: (i) meninges, (ii) blood vessels, (iii) choroid plexuses, (iv) circumventricular organs and (v) ependyma (neuroependyma in embryos). All five interfaces have distinctive morphological and physiological properties; the first th...

To the Editor The article by Stergiakouli et al¹ has created considerable media interest and consternation among pregnant women and mothers of young children in Australia.

Tissue loss after spinal trauma is biphasic, with initial mechanical/haemorrhagic damage at the time of impact being followed by gradual secondary expansion into adjacent, previously unaffected tissue. Limiting the extent of this secondary expansion of tissue damage has the potential to preserve greater residual spinal cord function in patients. Th...

Raw transcript data for PcTx1- and saline-treated adult rats 24 h after spinal cord injury Raw gene transcript data (Illumina Platform) for PcTx1-treated (n=3) and saline-treated (n=3) adult rats 24 h after mid-thoracic spinal cord injury. The top row shows the injury severity (SIS) score for each animal during the first 24 h post-injury. The seco...

Tissue loss after spinal trauma is biphasic, with initial mechanical/haemorrhagic damage at the time of impact being followed by gradual secondary expansion into adjacent, previously unaffected tissue. Limiting the extent of this secondary expansion of tissue damage has the potential to preserve greater residual spinal cord function in patients. Th...

Barrier mechanisms in the brain are important for its normal functioning and development. Stability of the brain’s internal environment, particularly with respect to its ionic composition, is a prerequisite for the fundamental basis of its function, namely transmission of nerve impulses. In addition, the appropriate and controlled supply of a wide...

The brain functions within a specialised environment tightly controlled by brain barrier mechanisms. Understanding the regulation of barrier formation is important for understanding brain development and may also lead to finding new ways to deliver pharmacotherapies to the brain; access of many potentially promising drugs is severely hindered by th...

In recent years there has been a resurgence of interest in brain barriers and various roles their intrinsic mechanisms may play in neurological disorders. Such studies require suitable models and markers to demonstrate integrity and functional changes at the interfaces between blood, brain, and cerebrospinal fluid. Studies of brain barrier mechanis...

The transcriptome of embryonic and adult rat lateral ventricular choroid plexus, using a combination of RNA-Sequencing and microarray data, was analyzed by functional groups of influx transporters, particularly solute carrier (SLC) transporters. RNA-Seq was performed at embryonic day (E) 15 and adult with additional data obtained at intermediate ag...

In the adult the interface between the cerebrospinal fluid and the brain is lined by the ependymal cells, which are joined by gap junctions. These intercellular connections do not provide a diffusional restrain between the two compartments. However, during development this interface, initially consisting of neuroepithelial cells and later radial gl...

Careful examination of relevant literature shows that many of the most cherished concepts of the blood-brain barrier are incorrect. These include an almost mythological belief in its immaturity that is unfortunately often equated with absence or at least leakiness in the embryo and fetus. The original concept of a blood-brain barrier is often attri...

Developmental studies of spinal cord injury in which regrowth of axons occurs across the site of transection rarely distinguish between the recovery of motor-controlling pathways and that of ascending axons carrying sensory information. We describe the morphological changes that occur in the dorsal column (DC) of the grey short-tailed opossum, Mono...

To maintain the precise internal milieu of the mammalian central nervous system, well-controlled transfer of molecules from periphery into brain is required. Recently the soluble and cell-surface albumin-binding glycoprotein SPARC (secreted protein acidic and rich in cysteine) has been implicated in albumin transport into developing brain, however...

This study describes a combined transcriptome and proteome analysis of Monodelphis domestica response to spinal cord injury at two different postnatal ages. Previously we showed that complete transection at postnatal day 7 (P7) is followed by profuse axon growth across the lesion with near-normal locomotion and swimming when adult. In contrast, at...

Use of a virtual reality physical ride-on sailing simulator as a rehabilitation tool for recreational sports and community reintegration: a pilot study. Am J Phys Med Rehabil 2013;92:1104Y1109. Participation in sailing by people with disabilities, particularly in small sailboats, is widely regarded as having positive outcomes on self-esteem and gen...

Participation in sailing by people with disabilities, particularly in small sailboats, is widely regarded as having positive outcomes on self-esteem and general health for the participants. However, a major hurdle for people with no previous experience of sailing, even by those without disabilities, is the perception that sailing is elitist, expens...

For a long time the brain has been considered an immune-privileged site due to a muted inflammatory response and the presence of protective brain barriers. It is now recognized that neuroinflammation may play an important role in almost all neurological disorders and that the brain barriers may be contributing through either normal immune signaling...

Complete spinal transection in the mature nervous system is typically followed by minimal axonal repair, extensive motor paralysis and loss of sensory functions caudal to the injury. In contrast, the immature nervous system has greater capacity for repair, a phenomenon sometimes called the infant lesion effect. This study investigates spinal injuri...

Labelling of brainstem neurons. A: Schematic of labelling procedure. B: Number of labelled brainstem neurons in control, P7-injured and P28-injured opossums. Mean ± sem; *P≤0.05 vs control; #P≤0.05 vs P7-inj, by One-way ANOVA. (TIF)

Re-transection of P28-injured opossum. Video footage P28-injured opossum before and after re-transection of the spinal cord at the same site as the original transection. A control opossum walking on the treadmill at the same speed is shown for comparison in order to highlight the decreased FL–HL coordination. (MP4)

The choroid plexuses are the interface between the blood and the cerebrospinal fluid (CSF) contained within the ventricular spaces of the central nervous system. The tight junctions linking adjacent cells of the choroidal epithelium create a physical barrier to paracellular movement of molecules. Multispecific efflux transporters as well as drug-me...

We provide comprehensive identification of embryonic (E15) and adult rat lateral ventricular choroid plexus transcriptome, with focus on junction-associated proteins, ionic influx transporters and channels. Additionally, these data are related to new structural and previously published permeability studies. Results reveal that most genes associated...

Junction specific genes. A dataset containing junction transcripts from Illumina screen that were statistically enriched in either the embryo (E15) or adult, as identified by GEO annotations. (XLSX)

Ubiquitin, an 8.5 kDa protein associated with the proteasome degradation pathway has been recently identified as differentially expressed in segment of cord caudal to site of injury in developing spinal cord. Here we describe ubiquitin expression and cellular distribution in spinal cord up to postnatal day P35 in control opossums (Monodelphis domes...

It has been shown previously that after spinal cord injury, the loss of grey matter is relatively faster than loss of white matter suggesting interventions to save white matter tracts offer better therapeutic possibilities. Loss of white matter in and around the injury site is believed to be the main underlying cause for the subsequent loss of neur...

Electron micrographs of axons at different pathological stages, illustrating what appears to be a common pathological process of necrotic axons. In the control spinal cord the largest axons found within white matter are around 6–7 µm. After injury, many axons swell (stage 1) and the axoplasm becomes denser with organelles clustering in the centre o...

The choroid plexus epithelium controls the movement of solutes between the blood and the cerebrospinal fluid. It has been considered as a functionally more immature interface during brain development than in adult. The anatomical basis of this barrier is the interepithelial choroidal junction whose tightness has been attributed to the presence of c...