Dodecyl creatine ester, a promising treatment to deliver creatine to neurons, achieves pharmacology efficacy in creatine transporter deficiency.

Dodecyl creatine ester (DCE) is a creatine prodrug currently developed for brain diseases, including creatine transporter deficiency (CTD), an incurable rare genetic disease. A dual strategy combining a prodrug to bypass the non-functional creatine transporter and its delivery via the nose-to-brain pathway has been proposed to replenish creatine levels in cerebral cells, particularly in neurons of CTD patients. In vitro and in vivo studies in various animal models, including wild-type non-human primates and creatine transporter deficient mice, show that formulated DCE, when administered intranasally, achieves significant cerebral distribution up to the target cells, the neurons, and modulates the expression of neuronal markers related to cognitive function at doses intended for patients.

Impaired brain glucose metabolism as a biomarker for evaluation of dodecyl creatine ester in creatine transporter deficiency: Insights from patient brain-derived organoids and in vivo [18F]FDG PET imaging in a mouse model.

Creatine transporter deficiency (CTD) is an inborn error of creatine (Cr) metabolism in which Cr is not properly distributed to the brain due to a mutation in the Cr transporter (CrT) SLC6A8 gene. CTD is associated with developmental delays and with neurological disability in children. Dodecyl creatine ester (DCE), as a Cr prodrug, is a promising drug to treat CTD after administration by the nasal route, taking advantage of the nose-to-brain pathway.

Tests for learning and memory in rodent regulatory studies.

For decades, regulatory guidelines for safety assessment in rodents for drugs, chemicals, pesticides, and food additives with developmental neurotoxic potential have recommended a single test of learning and memory (L&M). In recent years some agencies have requested two such tests. Given the importance of higher cognitive function to health, and the fact that different types of L&M are mediated by different brain regions assessing higher functions represents a step forward in providing better evidence-based protection against adverse brain effects.

A Gad2 specific Slc6a8 deletion recapitulates the contextual and cued freezing deficits seen in Slc6a8 mice.

The creatine (Cr)-phosphocreatine shuttle is essential for ATP homeostasis. In humans, the absence of brain Cr causes significant intellectual disability, epilepsy, and language delay. Mutations of the creatine transporter (SLC6A8) are the most common cause of Cr deficiency.

Deciphering neuronal deficit and protein profile changes in human brain organoids from patients with creatine transporter deficiency.

Creatine transporter deficiency (CTD) is an X-linked disease caused by mutations in the SLC6A8 gene. The impaired creatine uptake in the brain results in intellectual disability, behavioral disorders, language delay, and seizures. In this work, we generated human brain organoids from induced pluripotent stem cells of healthy subjects and CTD patients.

Dodecyl creatine ester improves cognitive function and identifies key protein drivers including KIF1A and PLCB1 in a mouse model of creatine transporter deficiency.

Creatine transporter deficiency (CTD), a leading cause of intellectual disability is a result of the mutation in the gene encoding the creatine transporter SLC6A8, which prevents creatine uptake into the brain, causing mental retardation, expressive speech and language delay, autistic-like behavior and epilepsy. Preclinical and data indicate that dodecyl creatine ester (DCE) which increases the creatine brain content, might be a therapeutic option for CTD patients. To gain a better understanding of the pathophysiology and DCE treatment efficacy in CTD, this study focuses on the identification of biomarkers related to cognitive improvement in a Slc6a8 knockout mouse model (Slc6a8-/y) engineered to mimic the clinical features of CTD patients which have low brain creatine content.

Latrophilin-3 heterozygous versus homozygous mutations in Sprague Dawley rats: Effects on egocentric and allocentric memory and locomotor activity.

Latrophilin-3 (LPHN3) is a brain specific G-protein coupled receptor associated with increased risk of attention deficit hyperactivity disorder (ADHD) and cognitive deficits. CRISPR/Cas9 was used to generate a constitutive knockout (KO) rat of Lphn3 by deleting exon 3, based on human data that LPHN3 variants are associated with some cases of ADHD. Lphn3 KO rats are hyperactive with an attenuated response to ADHD medication and have cognitive deficits.

Review of Conventional and High Dose Rate Brain Radiation (FLASH): Neurobehavioural, Neurocognitive and Assessment Issues in Rodent Models.

Ionising radiation causes secondary tumours and/or enduring cognitive deficits, especially in children. Proton radiotherapy reduces exposure of the developing brain in children but may still cause some lasting effects. Recent observations show that ultra-high dose rate radiation treatment (≥40 Gy/s), called the FLASH effect, is equally effective at tumour control but less damaging to surrounding tissue compared with conventional dose rate protons (0.

Enhanced Transient Striatal Dopamine Release and Reuptake in Knockout Rats.

Latrophilin-3 (LPHN3) is an adhesion G protein coupled receptor involved in regulating neuroplasticity. Variants of are associated with increased risk of attention-deficit hyperactivity disorder. Data from mouse, zebrafish, , and rat show that disruption of LPHN3 results in hyperactivity, and in the Sprague-Dawley knockout rat, exhibit deficits in learning and memory and changes in dopamine (DA) markers in the neostriatum.

Male mice placed on a ketogenic diet from postnatal day (P) 21 through adulthood have reduced growth, are hypoactive, show increased freezing in a conditioned fear paradigm, and have spatial learning deficits.

The ketogenic diet (KD) is a non-pharmacological treatment for specific types of epilepsy. In addition, it has been shown to be effective in mitigating other neurologic disorders. The KD is also effective in reducing body mass, leading to an increase in use by the general population for weight loss.

Litter effects: Comments on Golub and Sobin's "Statistical modeling of litter as a random effect in mixed models to manage "intralitter likeness"".

The importance of litter effects (clustering of variance among offspring in rodents) has been known for decades. The standard approach was to treat the entire litter as a unit or to select one male and one female from each litter to prevent oversampling. These methods work but are imperfect.

Deletion of the Creatine Transporter (Slc6a8) in Dopaminergic Neurons Leads to Hyperactivity in Mice.

The lack of cerebral creatine (Cr) causes intellectual disability and epilepsy. In addition, a significant portion of individuals with Cr transporter (Crt) deficiency (CTD), the leading cause of cerebral Cr deficiency syndromes (CCDS), are diagnosed with attention-deficit hyperactivity disorder. While the neurological effects of CTD are clear, the mechanisms that underlie these deficits are unknown.

Impairment of cognitive flexibility in type 2 diabetic db/db mice.

Impaired executive function is a major peril for patients with type 2 diabetes, reducing quality of life and ability for diabetes management. Despite the significance of this impairment, few animal models of type 2 diabetes examine domains of executive function such as cognitive flexibility or working memory. Here, we evaluated these executive function domains in db/db mice, an established model of type 2 diabetes, at 10 and 24 weeks of age.

A Test of Dietary Monosodium Glutamate Developmental Neurotoxicity in Rats: A Reappraisal.

In 1979, we tested dietary monosodium glutamate (MSG) for developmental neurotoxicity in rats. The study was recently cited for establishing a No Observable Adverse Effect Level (NOAEL) for MSG as a food additive resulting in a change in the acceptable daily intake (ADI). Therefore, I re-evaluated the study [Vorhees et al.

Introduction and Summary of the 2018 Dietary Glutamate Workshop.

The 2018 Dietary Glutamate Workshop was organized and sponsored by the International Glutamate Technical Committee to provide a platform for a broad expert discussion on all relevant aspects of glutamate metabolism and safety in human nutrition. The participants reached a consensus with previous safety evaluations conducted by the global expert bodies, but contradicted the 2017 re-evaluation of dietary glutamates by the European Food Safety Authority, which proposed a group acceptable daily intake (ADI) of 30 mg/kg body weight per day. The participants of the Workshop concluded that the present knowledge on metabolism, kinetics, developmental and general toxicity of dietary glutamates did not warrant a change in the previous ADI of "not specified.

Effects of Acute Exposure of Permethrin in Adult and Developing Sprague-Dawley Rats on Acoustic Startle Response and Brain and Plasma Concentrations.

Permethrin is a type I (noncyano) pyrethroid that induces tremors at high concentrations and increases acoustic startle responses (ASRs) in adult rodents, however its effects in young rats have been investigated to a limited extent. ASR and tremor were assessed in adult and postnatal day (P)15 Sprague-Dawley rats at oral doses of 60, 90, or 120 mg/kg over an 8 h period. Permethrin increased ASR in adults, regardless of dose, and 20% of the high-dose rats showed tremor at later time points.