The Novel Cyclophilin D Inhibitor CC-2055 Exerts Anti-Seizure Effects in the Mouse Pilocarpine Model of Epilepsy Via Rescue of Hippocampal Parvalbumin-Positive Interneurons
Abstract number :
1.442
Submission category :
1. Basic Mechanisms / 1D. Mechanisms of Therapeutic Interventions
Year :
2022
Submission ID :
2232914
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:28 AM
Authors :
Jaehyouk Choi, PhD – University of California San Diego; Shuhe Wang, BS – Lab technician, Neurosciences, University of California San Diego; Yueyang Cai, BS – Lab technician, Neurosciences, University of California San Diego; Hans Fliri, PhD – Cypralis; Matthew Shtrahman, MD,PhD – Assistant Adjunct Professor, Neurosciences, University of California San Diego; Jong Rho, MD – Professor, Neurosciences, University of California San Diego
This is a Late Breaking abstract
Rationale: The mitochondrial permeability transition pore (mPTP) is a non-specific, large-conductance multimeric complex that when activated induces apoptotic cell death (PMID: 32625108, PMID: 30558250). Cyclophilin D (CypD) is a mitochondrial peptidyl-prolyl cis-trans isomerase that is a key regulator of mPTP opening. Intriguingly, CypD is highly expressed in parvalbumin-positive (PV+) GABAergic interneurons in hippocampus (PMID: 31818974). Earlier, we reported that pharmacological inhibition of CypD with cyclosporin A or N-methyl-4-isoleucine-cyclosporin (NIM811) renders anti-seizure effects in epileptic Kcna1-null mice (PMID: 25899847). Here, we asked whether a novel, brain-penetrant and selective CypD antagonist, CC-2055 (Cypralis, Ltd; UK) can decrease the frequency of spontaneous recurrent seizures (SRS) in the mouse pilocarpine model of epilepsy._x000D_
Methods: Eight-week-old C57BL/6 mice were injected with pilocarpine (275 mg/kg) to induce status epilepticus. A prefabricated head-mount was surgically implanted in the mice 3 weeks after pilocarpine treatment, and continuous video-EEG monitoring was initiated a week later for 7 days. Daily IP administration of CC-2055 (30 mg/kg) began when the mice (N=6) had at least one Stage 3-5 Racine seizure for 2 consecutive days. A control group of sham (vehicle)-treated mice (N=5) also underwent video-EEG monitoring after pilocarpine induction. Six days after the conclusion of CC-2055 treatment, mice were perfusion-fixed for IHC to assess the population of PV+ interneurons. In a separate cohort of similarly treated and aged pilocarpine mice, recordings of CA1 hippocampal pyramidal neurons were made in acute hippocampal brain slices using standard electrophysiological techniques. CC-2055 (1 μM) was bath applied for 10 min before recordings commenced.
Results: SRS began approximately 5 weeks after pilocarpine treatment. CC-2055 administration significantly decreased the average daily sezuire frequency 1.4±1.2 compared to 10.4±6.3 Stage 3-5 seizures in sham-treated animals. Interenstingly, the CC-2055 treatment led to an increase in PV+ cells in CA1 hippocampus compared to controls. In electrophysiological experiments, CA1 pyramidal cells more depolarized after pilocarpine mice led to a normalization of the resting membrane potential (RMP): 63±3.19 mV before vs. 65±4.09 mV CC-2055 treatment (N=3). Further, the rheobase current levels were 39±6.01 pA before treatment and 63±3.14 pA after CC-2055 administration (N=7)._x000D_
Conclusions: The novel CypD antagonist, CC-2055, induces anti-seizure effects in the mouse pilocarpine model of epilepsy. CC-2055 also appears to restore PV+ interneuron numbers in CA1 hippocampus and reverses the electrophysiological changes in CA1 pyramidal cells from pilocarpine-treated mice. Taken together, our preliminary results further support the scientific rationale for the development of CypD antagonists as novel anti-seizure medications.
Funding: Rady Children's Hospital Start-up Funding
Basic Mechanisms