Abstracts

Rationale: Rationale: Acthar Gel (ACTH) - containing a 39 amino acid peptide derived from pro-opiomelanocortin - is efficacious in the treatment of infantile spasms, an age-dependent catastrophic epileptic syndrome. A retrospective clinical study has suggested that ACTH might enhance cognitive function (PMID:19348622), but it is uncertain whether this occurs independent of its anticonvulsant activity. We asked whether ACTH might exert anticonvulsant and/or nootropic effects in intrinsically epileptic Kcna1-null mice. Methods: Methods: Heterozygous breeding pairs generated Kcna1-null (KO) mice. Two parasagittal electrodes and subcutaneous wireless transmitters were implanted at P28. Following a 2-day recovery period, baseline seizure activity was assessed over 72 hrs using wireless video-EEG recording techniques. Following the initial recording period, KO mice (n=4) were treated with 4 IU/kg ACTH IP four times daily for 7 days followed by a second 72-hr video-EEG recording (P37-40). An age-matched group of KO mice (n=3) were injected with saline under the same experimental conditions. After video-EEG monitoring, both ACTH-treated and control KO mice were sacrificed and long-term potentiation (LTP) was evoked in CA1 hippocampus by high frequency stimulation (HFS, 1 sec, 100 Hz) using standard electrophysiological techniques. Excitatory post-synaptic potential (EPSP) amplitudes during the maintenance phase of LTP were compared amongst the 2 cohorts using ANOVA. Results: Results: Baseline video-EEG data revealed an average of 2-3 spontaneous generalized seizures per day. Interestingly, no significant changes in seizure frequency were detected following ACTH treatment. HFS induced normal LTP responses in CA1 hippocampal slices from WT mice; however, LTP maintenance was significantly impaired in KO mice. ACTH produced a partial but significant recovery of LTP maintenance in KO animals; EPSP amplitudes were significantly different (p<0.05) between WT vs. KO and ACTH-treated vs. KO groups. Conclusions: Conclusions: ACTH exerts partial protective effects against intrinsic LTP impairment in Kcna1-null mice, suggesting that this peptide may provide nootropic effects in epileptic brain. Moreover, ACTH does not significantly reduce the frequency of spontaneous recurrent seizures in this KO model, arguing against seizure reduction being a confounding variable in our LTP experiments. Further studies involving additional animal models are necessary to further delineate the functional neuroprotective effects of ACTH. Supported by Questcor Pharmaceuticals, Inc.