Lithium Orotate as an Improved Therapeutic Agent in the Treatment of Mania: Preclinical Evidence from a Murine Model
| dc.contributor.committeeMember | Howland, John | |
| dc.contributor.committeeMember | Lodhi, Rohit | |
| dc.contributor.committeeMember | Taghibiglou, Changiz | |
| dc.contributor.committeeMember | Sawicki, Grzegorz | |
| dc.contributor.committeeMember | Barr, Alasdair | |
| dc.creator | Pacholko, Anthony Gordon | |
| dc.date.accessioned | 2023-10-12T22:00:35Z | |
| dc.date.available | 2023-10-12T22:00:35Z | |
| dc.date.copyright | 2023 | |
| dc.date.created | 2023-08 | |
| dc.date.issued | 2023-10-12 | |
| dc.date.submitted | August 2023 | |
| dc.date.updated | 2023-10-12T22:00:35Z | |
| dc.description.abstract | Lithium carbonate (LiCO) is a mainstay therapeutic for the prevention of mood-episode recurrence in bipolar disorder (BD). Unfortunately, lithium therapy is plagued by high rates of treatment non-compliance due to the unpleasant adverse effects associated with presently prescribed medications. Given that lithium-induced toxicities correlate with serum exposure, a lithium-based therapeutic that displays similar efficacy concurrent with lesser dosing requirements would likely improve treatment regimen adherence. Lithium orotate (LiOr) may meet this criteria, as previous research suggests it to possess unique uptake characteristics that may enable reductions in dosing and subsequent amelioration of toxicity. Thus, we hypothesized that LiOr is more potent than LiCO due to differential transport, allowing mitigation of side effect incidence consequent to lesser dosing requirements. Dose response curves were established for LiOr and LiCO in male and female mice using an amphetamine-induced hyperlocomotion (AIH) model; AIH captures manic elements of BD and is sensitive to a dose-dependent lithium block. LiCO induced a partial attenuation of AIH at doses of 15 mg/kg in males and 20 mg/kg in females. In contrast, LiOr elicited a near complete blockade at concentrations of just 1.5 mg/kg in both sexes, signifying superior potency and efficacy. Prior application of inhibitors of organic anion transporting polypeptides, or inhibition of orotate uptake into the pyrimidine biosynthesis pathway, completely abolished the effects of LiOr on AIH while sparing those of LiCO, thereby confirming the differential transport and compartmentalization of the two compounds. As proposed in our hypothesis, the increased potency of LiOr translated to improved tolerability: after 14 consecutive days of once daily administration, LiCO, but not LiOr, elicited polydipsia in both sexes, elevated serum creatinine expression in males, and increased serum TSH levels in females. In summation, LiOr demonstrates superior efficacy, potency, and tolerability to LiCO in both male and female mice, likely because of select transport-mediated uptake and incorporation into the pyrimidine biosynthesis pathway. | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.uri | https://hdl.handle.net/10388/15134 | |
| dc.language.iso | en | |
| dc.subject | Lithium | |
| dc.subject | orotic acid | |
| dc.subject | bipolar | |
| dc.subject | mania | |
| dc.title | Lithium Orotate as an Improved Therapeutic Agent in the Treatment of Mania: Preclinical Evidence from a Murine Model | |
| dc.type | Thesis | |
| dc.type.material | text | |
| thesis.degree.department | Anatomy, Physiology, and Pharmacology | |
| thesis.degree.discipline | Anatomy, Physiology, and Pharmacology | |
| thesis.degree.grantor | University of Saskatchewan | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Doctor of Philosophy (Ph.D.) |