Canagliflozin attenuates haloperidol-induced motor and spatial working memory deficits in mice: Evidence of its role in the treatment of Parkinson’s disease

Abstract

Canagliflozin (CANA), a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, has been widely reported for its neuroprotective activity evidenced by its antioxidant and anti-inflammatory properties in brain tissue injury. Thus, it is a promising therapeutic candidate in the treatment of neurodegenerative diseases. This study examined the protective effect of CANA on haloperidol-induced Parkinsonism in mice. Forty-two male mice were divided randomly into seven groups: group 1 - normal control; vehicle (10 mL/kg, p.o.), group 2 - vehicle (pathological control; 10 mL/kg, per oral), groups 3–5, received CANA (25, 50, and 100 mg/kg, p.o., respectively), and the sixth and seventh groups received trihexyphenidyl (THP, 1 mg/kg, p.o., standard drug), and CANA 100 mg/kg respectively, for 21 consecutive days. Animals in groups 2–6 were given haloperidol (1 mg/kg, i.p.) daily, one hour after pretreatment for 21 days. Spontaneous motor functions assessed with bar and rotarod test as well as working memory by Y-maze test. Thereafter, blood and discrete brain regions were collected for biochemical assays. CANA (25, 50, and 100 mg/kg) demonstrated significant reduction in cataleptic scores in both acute (22, 58, and 76 %, respectively) and chronic (46, 61, and 69 %, respectively) in bar tests at 120 minutes. CANA improved motor coordination through prolongation of latency to fall in the rotarod test. Similarly, haloperidol-induced working memory impairment was reversed by CANA evidenced in significant increase percent alternation behaviour and counteracted dopamine depletion by 57 and 68 % at 50 and 100 mg/kg, respectively. Furthermore, CANA significantly attenuated haloperidol-induced oxidative stress and TNF-α induction. It is of note that CANA did not induce hypoglycaemia in any of the treatment group. Findings from our study demonstrated the ability of canagliflozin to control muscle spasticity/weakness and working memory impairment in Parkinsonism through attenuation of oxidative stress and neuroinflammation.