The molecular approach prolongs the antidepressant effects of ketamine in mice by weeks

Researchers at the University of Vanderbilt identified a molecular approach to extend the antidepressant effects of ketamine in mice by applying BCI, a compound that inhibits Dusp6 to maintain the activation of the ERK track. The results suggest that BCI modulates the duration of the synaptic and behavioral effects of ketamine, potentially reducing the need for repeated dosage and associated side effects.

Major depressive disorder (MDD) significantly contributes to global disability, affecting millions in the world. Conventional antidepressants did not relieve symptoms in around 30% of patients, resulting in resistant treatment. Ketamine, initially developed as a dissociative anesthetic, has demonstrated rapid antidepressant effects in CT cases and treatment resistant.

A single intravenous dose can produce therapeutic effects in a few hours, but these effects are generally calm in a few days, requiring repeated administration. The recurrent dosage increases the risk of undesirable results, in particular dissociation and dependence.

In the study, “improved ERK activity extends the antidepressant effects of ketamine by increasing synaptic plasticity”, published in ScienceResearchers conducted a controlled preclinical study to determine whether the improvement in ERK signaling through the pharmacological inhibition of DUSP6 could extend the antidepressant effects of ketamine in mice.

The mice were assigned to four treatment conditions: saline, ketamine, BCI solution and a combination of BCI and ketamine. Group sizes varied according to the experimental procedure, including electrophysiological recordings, behavioral assessments and synaptic analysis. Ketamine has been administered by intraperitoneal to 5 mg / kg.

The levels of phosphorylation ERK were measured by Immunotransfert in the CA1 region of the Hippocampus at six o’clock and 24 hours after treatment.

Electrophysiological recordings of Synaptic Potentization CA1 were made using extracellular field records in hippocampal slices. Behavioral assessments included a forced swimming test and a novelty deleted feeding test, administered at 24 hours, two weeks and four weeks after treatment. Synaptic alterations have been evaluated using superresolution microscopy to assess the expression and synaptogenesis of surface and glua2 glua1.

ERK’s phosphorylation in the CA1 region has increased by 50% in the BCI + Ketamine group compared to ketamine alone at six hours after treatment. The levels of phosphorylation ERK returned to the basic line in all groups at 24 hours, except in the BCI + Ketamine group, which maintained an elevation of 25%.

A 157% increase in Synaptic Potentization CA1 was observed in the BCI + Ketamine group compared to ketamine alone at 24 hours after treatment. Mouses receiving ketamine alone presented a 58% increase in synaptic potentiation compared to saline witnesses.

The behavioral tests have indicated a reduction in the time of immobility in the forced swimming test in the BCI + Ketamine group compared to ketamine alone, a meaning emerging at two weeks and persistent at four weeks and eight weeks after treatment. No significant reduction was observed at 24 hours.

A novelty deleted feeding test revealed reduced latency to eat in the BCI + Ketamine group compared to witnesses two and four weeks.

Superresolution microscopy has shown a significant increase in GLU1 expression of GLUA1 surface and glua2 in CA1 synapses in the BCI + Ketamine group compared to all other groups at 24 hours after treatment.

Synaptogenesis, measured as the number of bassoon and homer1 clusters, was raised by 32% in the BCI + Ketamine group compared to the Salin Witness Group.

The targeting of ERK signaling by the inhibition of DUSP6 has extended the antidepressant effects of a single dose of ketamine in mice.

The results indicate that the increase in ERK Transitional activity can maintain synaptic potentiation and antidepressant type behavior up to eight weeks after treatment.

The extension of the effects of ketamine by ERK signaling modulation could reduce the need for repeated dosage. Human trials will determine whether DUSP6 targeting provides a safer and more sustained antidepressive strategy.

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