Dataset Information

A molecular approach to treating cognition in schizophrenia by calcium channel blockade: An open-label pilot study of the calcium-channel antagonist isradipine.

ABSTRACT: Cognitive impairment is a prominent and difficult to treat symptom in schizophrenia (SZ), which is directly related to functional disability. A variant in the gene coding for the alpha 1C subunit of L-type voltage gated calcium channel (CACNA1C) has been shown to negatively affect several neurocognitive domains. We conducted a 4-week, open label, pilot study of isradipine, a calcium channel blocker, to determine its feasibility, safety, and efficacy in improving cognition in SZ patients. Ten adults with stable SZ were started on a flexible dose of isradipine 5 mg/day (up to 10 mg/day) for 4 weeks. Weekly in-person visits tracked side effects and symptoms while neurocognition and functional capacity were assessed at baseline and week 4. There were no serious adverse events reported. Newly emergent side effects were dizziness (1 new incidence at week 4); difficulty sleeping (2 new incidences at week 4); and decreased energy (3 new incidences at week 4). 1 patient discontinued medication and was withdrawn. Treatment did not exacerbate clinical symptoms. Although power is limited, results indicate no clear benefit on neurocognition but a positive effect (baseline mean = 6.8 ± 1.3 to week 4 mean = 7.9 ± 1.1; t = 2.91, p = 0.017) on functional capacity was noted. This open label, pilot study provides preliminary evidence that isradipine is a relatively safe medication when used adjunctively in SZ patients. This study suggests that isradipine offers no clear cognitive and only minimal functional benefit; however, additional studies may be warranted in symptomatic patients, or those with specific CACNA1C genotypes.

SUBMITTER: Burdick KE

PROVIDER: S-EPMC7235642 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A molecular approach to treating cognition in schizophrenia by calcium channel blockade: An open-label pilot study of the calcium-channel antagonist isradipine.

Burdick Katherine E KE Perez-Rodriguez Mercedes M Birnbaum Rebecca R Shanahan Megan M Larsen Emmett E Harper Cierra C Poskus Jessica J Sklar Pamela P

Schizophrenia research. Cognition 20200518

Cognitive impairment is a prominent and difficult to treat symptom in schizophrenia (SZ), which is directly related to functional disability. A variant in the gene coding for the alpha 1C subunit of L-type voltage gated calcium channel (CACNA1C) has been shown to negatively affect several neurocognitive domains. We conducted a 4-week, open label, pilot study of isradipine, a calcium channel blocker, to determine its feasibility, safety, and efficacy in improving cognition in SZ patients. Ten adu ...[more]

PMID: 32455122

Similar Datasets

Project description:Objective: L-type calcium channels (LTCC) homeostatically regulate calcium on a beat by beat basis, but also provide Ca that over long time scales may contribute to transcriptional regulation. We previously showed that sustained LTCC blockade (CCB) elicits LTCC remodeling in ventricular cardiac myocytes (CM). Here we hypothesize that sustained CCB has broad effects on the expression of genes involved in calcium handling. Methods and Results: Therefore, we subjected adult mice to sustained CCB for 24 hours and performed gene expression profiling. In comparison to vehicle-only control animals, 231 genes were up-regulated, and 111 genes were down-regulated by sustained LTCC blockade (p <0.01). Gene ontology analysis suggested that the CaMKIIdelta signaling pathway was up-regulated in these cells. Unexpectedly, phosphorylation of phospholamban (PLN) at threonine17 (Thr17), an index of CaMKIIdelta activity, was not changed by sustained CCB; however, the degree of phosphorylation of the neighboring PLN-Ser16 substrate site for PKA was significantly reduced by sustained CCB compared to control. Gene expression profiling suggested no change in PKA, but it showed that protein phosphatase 2A (PP2A) mRNA increased, and immunoblots demonstrated that PP2Ac-alpha protein was significantly increased by sustained CCB. Consistent with elevated PP2Ac-alpha protein expression LTCC exhibited decreased phosphorylation of the C-terminal Ser1928 PKA substrate site. Conclusions: We conclude that sustained CCB elicits a spectrum of transcriptional events, including compensatory up-regulation of LTCC and PP2Ac-alpha. Although this study is restricted to mouse, these results suggest the new hypothesis that clinically-relevant sustained LTCC blockade in humans results in changes in gene regulation in the heart. Keywords: L-type calcium channel, calcium channel blockade, verapamil Female and male ICR mice (12-14 weeks age) weighing between 25 and 30 grams were anesthetized with a ketamine/xylazine mixture ( i.p.) allowing the subcutaneous implantation of miniosmotic pumps (Alzet, model 2001). The pumps were filled with either verapamil or vehicle (0.02% ascorbic acid). Control animals carried mini-pumps with vehicle and control animals were investigated in parallel with each set of experimental animals. Mini pumps delivered verapamil at 3.6 mg/kg/day for 24 (RNA)-48 (protein) hours. After treatment animals were anesthetized and weighed. Hearts were excised, rinsed, blotted dry, weighed, and then frozen on dry ice and the stored at -80oC until studied. Animals were anesthetized and euthanized according to animal protocols approved by the University of Kentucky Institutional Animal Care and Use Committee. This investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication NO. 85-23, revised 1996). Left ventricular free wall from female mice was rapidly excised and either snap frozen at -80oC or used immediately for RNA isolation. Three VER treated mice and 3 vehicle treated mice were used to generate RNA for microarray. Total RNA was isolated using the RNAqueous -4PCR kit (Ambion) and quantitated spectrophotometrically at 260nm. Contaminating genomic DNA was eliminated by DNase treatment (Ambion). RNA quality was assessed using the Agilent 2100 Bioanalyzer. Microarray data was obtained using the Affymetrix 430 V2 GeneChip (representing 45,101 probe sets), in accordance with the manufacturer’s specifications.

Dataset Information

A molecular approach to treating cognition in schizophrenia by calcium channel blockade: An open-label pilot study of the calcium-channel antagonist isradipine.

Publications

A molecular approach to treating cognition in schizophrenia by calcium channel blockade: An open-label pilot study of the calcium-channel antagonist isradipine.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets