Neurotrophic factor-based pharmacological approaches in neurological disorders

Abstract

Aging is a physiological event dependent on multiple pathways that are linked to lifespan and processes leading to cognitive decline. This process represents the major risk factor for aging-related diseases such as Alzheimer's disease, Parkinson's disease, and ischemic stroke. The incidence of all these pathologies increases exponentially with age. Research on aging biology has currently focused on elucidating molecular mechanisms leading to the development of those pathologies. Cognitive deficit and neurodegeneration, common features of aging-related pathologies, are related to the alteration of the activity and levels of neurotrophic factors, such as brain-derived neurotrophic factor, nerve growth factor, and glial cell-derived neurotrophic factor. For this reason, treatments that modulate neurotrophin levels have acquired a great deal of interest in preventing neurodegeneration and promoting neural regeneration in several neurological diseases. Those treatments include both the direct administration of neurotrophic factors and the induced expression with viral vectors, neurotrophins' binding with biomaterials or other molecules to increase their bioavailability but also cell-based therapies. Considering neurotrophins' crucial role in aging pathologies, here we discuss the involvement of several neurotrophic factors in the most common brain aging-related diseases and the most recent therapeutic approaches that provide direct and sustained neurotrophic support.

Keywords: Alzheimer’s disease; Parkinson’s disease; brain; brain-derived neurotrophic factor; glial cell-derived neurotrophic factor; nerve growth factor; neurotrophins; neurturin; stroke; tropomyosin receptor kinase receptors.

Figure 1

Neurotrophic factors and receptors: neurotrophic factors interaction with receptors, the implication of co-receptors, and their main activities in the brain. BDNF: Brain-derived neurotrophic factor; ECS: extracellular space; GDNF: glial cell-derived neurotrophic factor; GFRα1/2: GDNF family receptor alpha-1/2; ICS: intracellular space; NGF: nerve growth factor; NRTN: neurturin; NT-3/4: neurotrophin-3/4; Trk: tropomyosin receptor kinase receptors.

Figure 2

Neurotrophic factors and age-related disorders: implication of each different neurotrophic factor with neurological disorders. BDNF: Brain-derived neurotrophic factor; GDNF: glial cell-derived neurotrophic factor; NGF: nerve growth factor; NRTN: neurturin.