TGN-020, an Inhibitor of the Water Channel Aquaporin-4, Accelerates Nigrostriatal Neurodegeneration in the Rat Model of Parkinson’s Disease

The water channel aquaporin-4 (AQP-4) plays a very important role in the mechanisms involved in water homeostasis in the brain and also participates in the clearance of brain parenchyma from various metabolites, including amyloidogenic proteins that contribute to the development of neurodegenerative diseases. The aim of this work was to find out the effect of AQP-4 pharmacological inhibition in the brain on the neurodegeneration rate and compensatory processes in the nigrostriatal system in the rat lactacystin model of Parkinson’s disease (PD). The PD model was reproduced in male Wistar rats using microinjections of the selective proteasome inhibitor lactacystin into the substantia nigra pars compacta (SNpc). To suppress AQP-4 activity, its inhibitor, TGN-020, was injected into the cerebrospinal fluid of the lateral ventricle of the brain. The immunohistochemical methods and behavioral tests were applied to assess neurodegenerative changes and motor deficit. The lactacystin-induced PD model was characterized by a pre-threshold death rate of dopamine (DA)-ergic neurons in the SNpc (27%) and their axons in the dorsal striatum (19%) compared to the level at the clinical stage, as well as by a lack of changes in the level of tyrosine hydroxylase (TH), a key enzyme of DA synthesis in SNpc neurons, and in motor function. Such pathophysiological signs are characteristic of the preclinical stage of PD. The use of TGN-020 in the rat lactacystin PD model accelerated the transition from the preclinical to clinical stages of PD, as evidenced by a progression of neurodegeneration in the nigrostriatal system, attenuation of compensatory processes, and the development of PD-like motor symptoms. These data indicate that AQP-4 plays an important role in the molecular mechanisms providing brain protection from neurotoxic factors, while a decrease in its activity can lead to a disruption of the glymphatic system’s functioning. AQP-4 water channel may prove to be a promising therapeutic target for the neuroprotection in PD and other neurodegenerative diseases.