Fyn kinase inhibition using AZD0530 improves recognition memory and reduces depressive-like behaviour in an experimental model of Parkinson's disease

Abstract

Fyn kinase has recently been established as a major upstream regulator of neuroinflammation in PD. This study aimed to determine if inhibition of Fyn kinase could lead to reduced neuroinflammation and improvements in motor and non-motor impairments in an early-stage model of PD. An experimental model of PD was produced using intra-striatal injection (4{micro}l) of the neurotoxin 6-OHDA (5{micro}g/{micro}l). Sprague Dawley rats (n=42) were given either vehicle, 6mg/kg or 12mg/kg of Fyn kinase inhibitor (AZD0530) daily for 32 days via oral gavage and tested on a battery of tasks assessing motor, cognitive and neuropsychiatric outcomes. AZD 0530 administration led to improvement in volitional locomotion and recognition memory, as well as a reduction in depressive-like behaviour. Pathologically, an inflammatory response was observed; however, there were no significant differences in markers of neuroinflammation between treatment groups. Taken together, results indicate a potential therapeutic benefit for use of Fyn kinase inhibition to treat non-motor symptoms of PD, although mechanisms remain to be elucidated. HIGHLIGHTSO_LIFyn kinase has recently been proposed as a major upstream regulator of microglial activation in Parkinsons disease (PD). C_LIO_LIThis study was the first to evaluate the effects of Fyn kinase inhibition in a rodent model of PD. C_LIO_LIFyn kinase inhibition using the Fyn kinase inhibitor AZD 0530 was capable of improving volitional locomotion and recognition memory and reducing depressive-like behaviour in a rodent model of PD. C_LIO_LIInterestingly, while increases in microglial activation were observed in this rodent model of PD, AZD 0530 did not significantly reduce this activation. C_LIO_LIThis suggests that the behavioural improvements associated with Fyn kinase inhibition may occur independently of neuroinflammation and may be attributable to other brain mechanisms, including actions on NMDA or 5-HT6 receptors. C_LI