Abstract
ABSTRACTFyn 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 (4µl) of the neurotoxin 6-OHDA (5µg/µl). 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.HIGHLIGHTSFyn kinase has recently been proposed as a major upstream regulator of microglial activation in Parkinson’s disease (PD).This study was the first to evaluate the effects of Fyn kinase inhibition in a rodent model of PD.Fyn 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.Interestingly, while increases in microglial activation were observed in this rodent model of PD, AZD 0530 did not significantly reduce this activation.This 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.
Publisher
Cold Spring Harbor Laboratory