Small Molecules and Peptides Targeting Glial Cell Line-Derived Neurotrophic Factor Receptors for the Treatment of Neurodegeneration

Abstract

Glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are able to promote the survival of multiple neuronal populations in the body and, therefore, hold considerable promise for disease-modifying treatments of diseases and conditions caused by neurodegeneration. Available data reveal the potential of GFLs for the therapy of Parkinson’s disease, neuropathic pain and diseases caused by retinal degeneration but, also, amyotrophic lateral sclerosis and, possibly, Alzheimer’s disease. Despite promising data collected in preclinical models, clinical translation of GFLs is yet to be conducted. The main reasons for the limited success of GFLs clinical development are the poor pharmacological characteristics of GFL proteins, such as the inability of GFLs to cross tissue barriers, poor diffusion in tissues, biphasic dose-response and activation of several receptors in the organism in different cell types, along with ethical limitations on patients’ selection in clinical trials. The development of small molecules selectively targeting particular GFL receptors with improved pharmacokinetic properties can overcome many of the difficulties and limitations associated with the clinical use of GFL proteins. The current review lists several strategies to target the GFL receptor complex with drug-like molecules, discusses their advantages, provides an overview of available chemical scaffolds and peptides able to activate GFL receptors and describes the effects of these molecules in cultured cells and animal models.

Neurotrophic Factors in Parkinson’s Disease: Clinical Trials, Open Challenges and Nanoparticle-Mediated Delivery to the Brain

“…Degeneration of dopamine neurons starts from their synapses and the axons in caudate putamen ( Figure 1 ), whereas cell bodies in the SNpc degenerate later. NTFs are not able to reverse the apoptosis of completely degenerated neurons; instead, they restore the axons of the stressed and degenerating dopamine neurons and their contacts ( Sidorova and Saarma, 2020 ). Thus, the degenerating axons in caudate putamen are the main targets of NTFs, and according to current understanding, the NTFs should be delivered to the axons of the neurons into caudate putamen (discussed in more details below).…”

“…In addition to NGF that was tested in one patient, four growth factors, glial cell line-derived neurotrophic factor (GDNF), neurturin (NRTN), platelet-derived growth factor (PDGF-BB), and CDNF have been tested in clinical trials in PD patients. The results of the clinical studies with GDNF, NRTN, and PDGF-BB were summarized by Sullivan and Toulouse (2011) , recently updated by Huttunen and Saarma (2019) , Barker et al (2020) , and Sidorova and Saarma (2020) and briefly summarized in Table 1 . The clinical benefit of NTFs in these clinical trials was mostly assessed using Unified Parkinson’s Disease Rating Scale (UPDRS) demonstrating the severity of motor symptoms.…”

Neuroprotective effects of pomegranate (Punica granatum L.) juice and seed extract in paraquat-induced mouse model of Parkinson’s disease

“…It was recorded that GDNF is an important factor for dopaminergic neuronal survival [ 18 ] and that the elevated level of GDNF could induce the function of dopaminergic neurons and might exhibit a neuroprotective role in PD animal models [ 53 ]. The results in the current experiment showed that both PSE and PJ increased the level of GDNF in the striatum of PQ-injected animals.…”

“…It has been reported that glial cell-derived neurotrophic factor (GDNF) exhibits a prominent neurorestoration and neuroprotection in multiple neurodegenerative diseases, including PD. [ 17 ] It was recorded that GDNF is a crucial factor for the survival of the dopaminergic neurons [ 18 ]. It was investigated in different PD clinical trials since the main hallmark for PD pathology is the dopaminergic neuronal loss in the brain [ 18 ].…”

“…[ 17 ] It was recorded that GDNF is a crucial factor for the survival of the dopaminergic neurons [ 18 ]. It was investigated in different PD clinical trials since the main hallmark for PD pathology is the dopaminergic neuronal loss in the brain [ 18 ]. Subsequently, it was vital to be assessed in the current animal model of PD and might be used as an indicator for the degeneration of dopamine neurons.…”