Objective: Neuroinflammation is a pathological hallmark of several neurodegenerative diseases. We speculated that reduction of calcium ion influx specifically in neurons should reduce inflammatory cellular signaling and ultimately lead to reduced neurodegeneration and to deceleration of disease phenotype.

Background: We have identified orally available compounds that specifically inhibit the N-type calcium channel CaV2.2 (NCC) in nanomolar concentrations without affecting the L-type calcium channel. Target engagement has been shown in vivo in a spinal nerve ligation (SNL) rat model and a sciatic inflammatory neuritis (SIN) rat model. The observed acute and therapeutic reversion of tactile allodynia shows that the orally applied compound hits the NCC also in vivo. The same compound and a second NCC inhibiting compound were tested also in different neurodegenerative animal models. There, we found very significant deceleration of the neurodegenerative phenotype as shown for example in the SHIRPA assay. Here, we present efficacy of one of our compounds in the SODG93A transgenic mouse model of ALS.

Methods: SOD1G93A mice were treated with the compound either intraperitoneally or orally and compared with placebo. In pre-tests and during treatment, the mice were tested longitudinally in different behavioral and motor coordination tests (SHIRPA test, open field test, rotarod test, pole test). Brain, cervical spinal cord and the M. gastrocnemius were analyzed histologically for ALS pathology. Several pro- and anti-inflammatory cytokines were analyzed in plasma samples.

Results: Treatment led to slower developing neurodegenerative phenotype based on the performance in the SHIRPA, rotarod and pole tests. Last not least, we observed retardation of the average disease onset in the treated animals. In addition, we will present treatment influence on pathology and cytokine levels in plasma.

Conclusions: We were able to show that the investigated NCC-inhibiting compound shows beneficial efficacy in the SOD1G93A mouse model, also upon oral application. These findings qualify the compound as a compound to be considered for further development and testing towards a disease modifying ALS treatment.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/reduction-of-neuroinflammation-by-selective-inhibition-of-the-n-type-calcium-channel-is-beneficial-in-various-animal-models-of-neurodegeneration-here-in-the-sod1g93a-transgenic-mouse-model-of-als/