HIP/PAP prevents excitotoxic neuronal death and promotes plasticity

Abstract

ObjectivesExcitotoxicity plays a significant role in the pathogenesis of perinatal brain injuries. Among the consequences of excessive activation of the N-methyl-d-aspartate (NMDA)-type glutamate are oxidative stress caused by free radical release from damaged mitochondria, neuronal death and subsequent loss of connectivity. Drugs that could protect nervous tissue and support regeneration are attractive therapeutic options. The hepatocarcinoma intestine pancreas protein/pancreatitis-associated protein I (HIP/PAP) or Reg3α, which is approved for clinical testing for the protection and regeneration of the liver, is upregulated in the central nervous system following injury or disease. Here, we examined the neuroprotective/neuroregenerative potential of HIP/PAP following excitotoxic brain injury.MethodsWe studied the expression of HIP/PAP and two of its putative effectors, cAMP-regulated phosphoprotein 19 (ARPP19) and growth-associated protein 43 (GAP-43), in the neonatal brain, and the protective/regenerative properties of HIP/PAP in three paradigms of perinatal excitotoxicity: intracerebral injection of the NMDA agonist ibotenate in newborn pups, a pediatric model of traumatic brain injury, and cultured primary cortical neurons.ResultsHIP/PAP, ARPP19, and GAP-43 were expressed in the neonatal mouse brain. HIP/PAP prevented the formation of cortical and white matter lesions and reduced neuronal death and glial activation following excitotoxic insults in vivo. In vitro, HIP/PAP promoted neuronal survival, preserved neurite complexity and fasciculation, and protected cell contents from reactive oxygen species (ROS)-induced damage.InterpretationHIP/PAP has strong neuroprotective/neuroregenerative potential following excitotoxic injury to the developing brain, and could represent an interesting therapeutic strategy in perinatal brain injury.

The Anti-Inflammatory Effects of the Small Molecule Pifithrin-µ on BV2 Microglia

“…LPS reduced MTT output by approximately 15%, an effect previously described [37,38], and PFT-µ had no significant effect in the 2-way ANOVA (fig. 1).…”

Reversible lesion in the splenium of the corpus callosum

“…Intracellular ATP depletion that leads to mitochondrial dysfunction and oxidative stress is induced by activated the glutamate–glutamine cycle (Haldipur et al, ; Rodrigo & Felipo, ). The excitotoxic action of receptors such as metabotropic glutamate receptors, glutamate on N ‐methyl‐ d ‐aspartate, α‐amino‐3‐ hydroxy‐5‐methyl‐4‐isoxazole propionic acid receptors, and aquaporins results in an influx of water into both astrocytes and neurons.…”

“…Intracellular ATP depletion that leads to mitochondrial dysfunction and oxidative stress is induced by activated the glutamate-glutamine cycle (Haldipur et al, 2014;Rodrigo & Felipo, 2007). The Cytotoxic edema is characterized by the intracellular accumulation of fluid and Na + , which results in cell swelling.…”

Enteric Delivery of Regenerating Family Member 3 alpha Alters the Intestinal Microbiota and Controls Inflammation in Mice With Colitis

“…The human secreted C-type lectin hREG3A (human regenerating family member 3 alpha), or hepatocarcinomaintestine-pancreas/pancreatitis-associated protein, is a 16-kDa carbohydrate-binding protein exhibiting remarkable anti-inflammatory activities in many eukaryote cell types, where hREG3A promotes tissue regeneration and repair. [19][20][21][22][23][24][25] It is expressed in Paneth's cells and the neuroendocrine cells of the small intestine physiologically, and in the large intestine in response to infection and inflammation. The mechanisms of reduction of inflammation by hREG3A are not fully understood.…”