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Uzay, B.

Publications and source records attributed to Uzay, B..

2 recordsLinked to original sources
bioRxiv2022

The Effect of P2X7 Antagonism on Subcortical Spread of Optogenetically-Triggered Cortical Spreading Depression and Neuroinflammation

Migraine is a neurological disorder characterized by episodes of severe headache. Cortical spreading depression (CSD), the electrophysiological equivalent of migraine aura, results in opening of pannexin-1 megachannels that release ATP and triggers parenchymal neuroinflammatory signaling cascade in the cortex. Migraine symptoms suggesting subcortical dysfunction bring subcortical spread of CSD under the light. Here, we investigated the role of purinergic P2X7 receptors on the subcortical spread of CSD and its consequent neuroinflammation using a potent and selective P2X7 antagonist, JNJ-47965567. P2X7 antagonism had no effect on the CSD threshold and characteristics but increased the latency to hypothalamic voltage deflection following CSD showing that ATP acts as a mediator in the subcortical spread. P2X7 antagonism also prevented hypothalamic neuronal activation following CSD, revealed by bilateral decrease in hypothalamic c-fos positive neuron count. P2X7 antagonism further stopped the CSD-induced neuroinflammation revealed by decreased nuclear translocation of NF-kappa B-p65 in astrocytes and decreased HMGB1 release. Following CSD we observed an increase in neuronal cytoplasmic P2X7R signal in cortex and subcortical structures (thalamus, hypothalamus, striatum, hippocampus) concordant with the neuroinflammation which is also prevented by P2X7R antagonism. In conclusion, our data suggest that P2X7R plays an imperative role in CSD-induced neuroinflammation, subcortical spread of CSD and CSD-induced hypothalamic neuronal activation hence can be a potential target in migraine treatment.

neuroscience↗
bioRxiv2022

NUDT6, the Antisense Protein of FGF2 Gene, Plays a Depressogenic Role by Promoting Inflammation and Suppressing Neurogenesis without Altering FGF2 Signaling

Fibroblast growth factor-2 (FGF2) is involved in the regulation of affective behavior and shows antidepressant effects through Akt and ERK1/2 pathways. NUDT6 is a protein encoded from FGF2 genes antisense strand and its role in the regulation of affective behavior is unclear. Here, we show that increasing NUDT6 expression in the hippocampus results in depression-like behavior in rats without changing FGF2 levels or activating its downstream effectors, Akt and ERK1/2. Instead, NUDT6 acts by inducing inflammatory signaling, specifically by increasing S100A9 levels, activating NF-{kappa}B and rising microglia number along with a reduction in neurogenesis. Conversely, inhibition of hippocampal NUDT6 expression by shRNA results in antidepressant effects and increases neurogenesis without altering FGF2 levels. Together these findings suggest that NUDT6 may play a role in major depression by inducing a proinflammatory state and serve as a novel therapeutic target for antidepressant development. This is the first report of an antisense protein acting through a different mechanism of action than regulation of its sense protein. The opposite effects of NUDT6 and FGF2 on depression-like behavior may serve as a mechanism to fine-tune affective behavior. Our findings open up new venues for studying the differential regulation and functional interactions of sense and antisense proteins in neural function and behavior as well as in neuropsychiatric disorders.

neuroscience↗