Can Growth Factors Cure Parkinson’s Disease?

Abstract

Growth factors (GFs) hold considerable promise for disease modification in neurodegenerative disorders because they can protect and restore degenerating neurons and also enhance their functional activity. However, extensive efforts applied to utilize their therapeutic potential in humans have achieved limited success so far. Multiple clinical trials with GFs were performed in Parkinson's disease (PD) patients, in whom diagnostic symptoms of the disease are caused by advanced degeneration of nigrostriatal dopamine neurons (DNs), but the results of these trials are controversial. This review discusses recent developments in the field of therapeutic use of GFs, problems and obstacles related to this use, suggests the ways to overcome these issues, and alternative approaches that can be used to utilize the potential of GFs in PD management. Neurotrophic Factors and Their Potential in Parkinson's Disease TherapyNeurodegeneration in Parkinson's disease (PD; Box 1) starts from the axons of dopamine (DA) neurons (DNs) in the putamen (Figure 1). When PD is diagnosed there is a 70-80% reduction in the putaminal DA level, approximately 70% decrease in the density of DA axons, but only 30% reduction in the number of DN cell bodies in the substantia nigra pars compacta (SNpc) [1,2]. Therefore, the remaining functional and dystrophic DNs represent an attractive target for supportive and neurorestorative (see Glossary) therapeutic approaches, respectively, which can be provided by growth factors (GFs) including neurotrophic factors (NTFs; Box 2).GFs have been extensively tested in several preclinical PD models (PD models are described in Box 3) and have shown considerable promise for disease modification. Some of them were also trialed in PD patients, but the therapeutic success of such interventions was rather limited. To critically evaluate the results of clinical trials conducted with GFs in PD patients it is important to understand key differences in pharmacology and mode of action of GF treatments compared with conventional small-molecule drugs. Importantly, GFs act in the organism via defined and physiologically relevant molecular pathways in contrast to other agents which are potentially neuroprotective for DN (e.g., an antidiabetic drug exenatide) [3]. Moreover, GFs not only protect, but also restore neurons, promote arborization and sprouting of their neurites, and enhance the functional activity of neurons. These points justify further attempts to translate GFs into drugs for PD treatment. HighlightsGrowth factors (GFs) supporting neuronal survival and increasing their functional activity are promising leads for the development of disease-modifying treatments for neurodegenerative disorders.Clinical use of GFs requires careful planning with regard to dosing, delivery paradigms and equipment, frequency of administration, and the development of patients' stratification criteria.Several alternatives to naturally occurring GFs, such as mutant proteins or small molecules targeting GF receptors, show promise in animal model...

Small-Molecule Inhibitors of the RNA M6A Demethylases FTO Potently Support the Survival of Dopamine Neurons

“…This model has some limitations, as embryonic rodent neurons are used and the growth factor deprivation or neurotoxin poisoning do not replicate the real pathological situation in Parkinson’s disease. Nevertheless, it is a widely used cellular model to test the efficacy of growth factors and small molecules before testing them in animal models of Parkinson’s disease [ 39 , 40 ]. It has been demonstrated that the preferred cellular substrate for FTO is not the m 6 A but its further modification N 6 2′-O-dimethyladenosine (m 6 Am), which is exclusively found adjacent to the 7-methylguanine (m7G) cap in mRNA [ 41 , 42 , 43 ].…”

“…GDNF has been shown to protect cultured embryonic dopamine neurons from growth factor deprivation induced apoptosis, as well as 6-OHDA-induced cell death in vitro and in vivo [ 38 , 40 ]. We, therefore, assessed the neuroprotective ability of different concentrations of FTO or ALKBH5 inhibitors in cultured growth factor deprived dopamine neurons.…”

Small-molecule inhibitors of the RNA m6A demethylase FTO potently support the survival of dopamine neurons

“…GDNF has been shown to protect cultured embryonic dopamine neurons from growth factor deprivation induced, as well as 6-OHDA-induced cell death in vitro and in vivo 40,52 . We, therefore, assessed the neuroprotective ability of different concentrations of FTO or AlkBH5 inhibitors in cultured growth factor deprived dopamine neurons.…”

“…It is interesting to note that the potency of FTO inhibitors 2 and 3 in protecting and rescuing DA neurons in vitro is comparable to that of GDNF. Since GDNF, when directly injected into the midbrain, protects dopamine neurons also in animal models of PD, 52,53 it is logical to assume that FTO and AlkBH5 inhibitors can also be neuroprotective in vivo . The main limitation in the clinical use of GDNF and other neurotrophic proteins in the treatment of PD is their inability to pass through the BBB.…”

“…Since mRNA and snRNA m 6 A modification may have impact on neuronal survival, it was therefore interesting to compare the effects of inhibition of these two RNA m 6 GDNF has been shown to protect cultured embryonic dopamine neurons from growth factor deprivation induced, as well as 6-OHDA-induced cell death in vitro and in vivo 40,52 . We, Similarly, in growth factor deprivation model, AlkBH5 inhibitors 7 and 8 at three tested concentrations increased the number of TH-positive neurons (Figures 7c and 7d, respectively).…”