Novel nanosized GDNF mimetics for the treatment of Parkinson’s disease: focus on...
Novel nanosized GDNF mimetics for the treatment of Parkinson’s disease: focus onto non-dopaminergic features
PD is the most common age-related neurodegenerative disorder that is characterized by four pathognomonic hallmarks: 1) motor and non-motor deficits; 2) progressive loss of nigrostriatal dopamine neurons; 3) pathological aggregates...
PD is the most common age-related neurodegenerative disorder that is characterized by four pathognomonic hallmarks: 1) motor and non-motor deficits; 2) progressive loss of nigrostriatal dopamine neurons; 3) pathological aggregates of the α-synuclein (α-syn) protein; 4) neuroinflammation and oxidative stress. There is no single treatment currently available (or being tested) that can affect mechanisms of the disease, promote regeneration or at least protection of dopamine (and other affected neurons), and alleviate both motor and non-motor symptoms. Importantly, non-motor symptoms severely alter the quality of life of the patients since they are even more debilitating than the motor ones and do not respond to dopaminergic-based therapies. One of the therapeutically potent approaches to combat PD is neurotrophic factors (NTFs)-based therapies, particularly the glial cell line-derived neurotrophic factor (GDNF). GDNF demonstrated encouraging survival-promoting effects on dopamine neurons in diverse PD animal models and held a great hope as a neuroprotective treatment. Also, GDNF has positive impact in a number of other neurons such as sensory, enteric, olfactory, etc., which degeneration or dysfunction is associated with the appearance of non-motor symptoms. Despite of the promising results, GDNF due to poor tissue distribution and inability to pass through the blood brain barrier should be delivered to the brain through a risky surgery. To overcome the delivery problems and finally utilize the potential of GDNF in PD management proposed project combines neurobiology, translational biology, and experimental pharmacology to develop nanosized GDNF mimetic-based drug candidate that will 1) positively impact the disease progression through mitigation of the pathogenesis associated with α-syn aggregations and neuroinflammation, 2) support the survival of human dopamine neurons in vitro and 3) alleviate motor and non-motor symptoms of PD in vivo.ver más
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