Inhibition of N-methyl-d-aspartate receptor activity resulted in aberrant neuronal migration caused by delayed morphological development in the mouse neocortex

Q3 · MEDICINE

Article

Author: Gonda, Y. ; Kohsaka, S. ; Waga, C. ; Tabata, H. ; Uchino, S. ; Ondo, Y. ; Nakajima, K. ; Hirasawa, T.

Embryonic and neonatal neocortical neurons already express functional N-methyl-D-aspartate (NMDA) receptors before they form synapses. To elucidate the role of NMDA receptors in neuronal migration in the developing neocortex, we visualized radially migrating neurons by transferring the enhanced green fluorescent protein (EGFP) gene into the ventricular zone (VZ) of the mouse neocortex using in utero electroporation at E15.5. Two days later, we prepared neocortical slices and examined the EGFP-positive cells using time-lapse imaging in the presence of the NMDA receptor antagonist Cerestat. The EGFP-positive cells generated in the VZ in the control slices exhibited a multipolar morphology, but within several hours they became bipolar (with a leading process and an axon-like process) and migrated toward the pial surface. By contrast, many of the multipolar cells in the Cerestat-treated slices failed to extend either process and become bipolar, and frequently changed direction, although they ultimately reached their destination even after Cerestat-treatment. To identify the molecules responding for mediating NMDA signaling during neuronal migration and the changes in morphology observed above, we here focused on Src family kinases (SFKs), which mediate a variety of neuronal functions including migration and neurite extension. We discovered that the activity of Src and Fyn was reduced by Cerestat. These findings suggest that NMDA receptors are involved in neuronal migration and morphological changes into a bipolar shape, and in the activation of Src and Fyn in the developing neocortex.

01 Feb 2010·StrokeQ1 · MEDICINE

Anti-Ischemic Effect of N -Methyl- d -Aspartate Receptor Blockade Is Potentiated by Caffeine

Q1 · MEDICINE

Article

Author: Piriyawat, Paisith ; Grotta, James C. ; Palusinski, Robert ; Strong, Roger ; Zhao, Xiurong ; Aronowski, Jaroslaw

Background and Purpose— Although caffeinol (a combination of a low dose of caffeine and ethanol) was shown to robustly reduce stroke damage in experimental models and is now in clinical evaluation for treatment of ischemic stroke, little is known about the potential mechanism of its action. Methods— We used an in vivo excitotoxicity model based on intracortical infusion of N -methyl- d -aspartate (NMDA) and a model of reversible focal ischemia to demonstrate NMDA receptor inhibition as a potential mechanism of caffeinol anti-ischemic activity. Results— Caffeinol reduced the size of excitotoxic lesion, and substitution of ethanol in caffeinol with the NMDA antagonists CNS-1102 and MK-801 but not with MgSO 4 produced treatment with strong synergistic effect that was at least as robust in reducing ischemic damage as caffeinol. This NMDA receptor antagonist and caffeine combination demonstrated a long window of opportunity, activity in spontaneously hypertensive rats, and, unlike caffeinol, was fully effective in animals chronically pretreated with ethanol. Conclusions— Our study suggests that antiexcitotoxic properties may underlie some of the anti-ischemic effect of caffeinol. This study provides strong evidence that the anti-ischemic effect of NMDA receptor blockers in general can be dramatically augmented by caffeine, thus opening a possibility for new use of NMDA-based pharmacology in the treatment of stroke.

01 Mar 2006·Toxicological SciencesQ2 · MEDICINE

Synergistic Interactions between Commonly Used Food Additives in a Developmental Neurotoxicity Test

Q2 · MEDICINE

Article

Author: McLean, W. Graham ; Howard, C. Vyvyan ; Lau, Karen ; Williams, Dominic P.

Exposure to non-nutritional food additives during the critical development window has been implicated in the induction and severity of behavioral disorders such as attention deficit hyperactivity disorder (ADHD). Although the use of single food additives at their regulated concentrations is believed to be relatively safe in terms of neuronal development, their combined effects remain unclear. We therefore examined the neurotoxic effects of four common food additives in combinations of two (Brilliant Blue and L-glutamic acid, Quinoline Yellow and aspartame) to assess potential interactions. Mouse NB2a neuroblastoma cells were induced to differentiate and grow neurites in the presence of additives. After 24 h, cells were fixed and stained and neurite length measured by light microscopy with computerized image analysis. Neurotoxicity was measured as an inhibition of neurite outgrowth. Two independent models were used to analyze combination effects: effect additivity and dose additivity. Significant synergy was observed between combinations of Brilliant Blue with L-glutamic acid, and Quinoline Yellow with aspartame, in both models. Involvement of N-methyl-D-aspartate (NMDA) receptors in food additive-induced neurite inhibition was assessed with a NMDA antagonist, CNS-1102. L-glutamic acid- and aspartame-induced neurotoxicity was reduced in the presence of CNS-1102; however, the antagonist did not prevent food color-induced neurotoxicity. Theoretical exposure to additives was calculated based on analysis of content in foodstuff, and estimated percentage absorption from the gut. Inhibition of neurite outgrowth was found at concentrations of additives theoretically achievable in plasma by ingestion of a typical snack and drink. In addition, Trypan Blue dye exclusion was used to evaluate the cellular toxicity of food additives on cell viability of NB2a cells; both combinations had a straightforward additive effect on cytotoxicity. These data have implications for the cellular effects of common chemical entities ingested individually and in combination.

100 Deals associated with Cerestat

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Brain Injuries, Traumatic	Phase 3	-	Cambridge Neuroscience	-
Brain Injuries, Traumatic	Phase 3	-	Cenes Ltd.	-
Stroke	Phase 3	-	Cambridge Neuroscience	-
Stroke	Phase 3	-	Cenes Ltd.	-

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