Harnessing neurogenesis for the possible treatment of Parkinson's disease

Abstract

The discovery of neurogenesis in the adult brain has created new possibilities for therapeutics in neurodegenerative diseases. Neural precursor cells, which have been found in various parts of the brain, e.g., the subventricular zone (SVZ) and substantia nigra (SN), have promising potential to replace the extensive loss of neurons occurring in neurodegenerative disorders. In Parkinson's disease (PD) the degeneration of nigral dopaminergic neurons and consequently the nigrostriatal pathway, which has been found to innervate proximally to the SVZ, causes motor and cognitive impairments. There is strong evidence that neurogenesis is impaired in PD, which has been related to the nonmotor symptoms of the disease. Recent evidence supports that this impairment in neurogenesis is partially caused by the lack of dopamine in one of the adult neurogenic niches, the SVZ. Thus, restoring the dopaminergic pathway in PD patients may have implications not only for motor function improvement, but for other cognitive and autonomic symptoms. Currently, there are no effective treatments that can stop or reverse the neurodegeneration process in the brain. Here we review the neurogenic process and observed alterations found in PD animal models and postmortem brains of PD patients. Finally, we review several attempts to stimulate the neurogenic process for nigral and/or striatal dopaminergic restoration by transgenic expression, exercise, or cell therapy.

Hippocampal Proliferation Is Increased in Presymptomatic Parkinson’s Disease and due to Microglia

“…In addition, several Parkinson-related pathogens induce degeneration of human neural stem cells (NSCs) [18] or reduce neurogenesis [19]. Stimulation of cellular plasticity on the other hand, for example through exercise, antidepressant treatment or high frequency stimulation, reverses impairments in neurogenesis in PD models [20] and may even benefit PD patients [21, 22]. …”

Hippocampal Adaptive Response Following Extensive Neuronal Loss in an Inducible Transgenic Mouse Model

“…Neurodegenerative disorders such as Alzheimer's disease [41], [42], Huntington's disease [43], [44] Parkinson's disease [45], [46], and epilepsy [47], [48] has been shown to alter neurogenesis. Neurogenesis has also been shown to be upregulated following brain injury, such as stroke [49], [50] and traumatic brain injury [51], [52].…”

Leucine rich repeat kinase 2 (LRRK2) inhibitors based on indolinone scaffold: Potential pro-neurogenic agents

“…Among these connections we considered as the most interesting one, the hypothesis that the pharmacological inhibition of LRRK2 may induce adult neurogenesis. There is evidence suggesting that neurogenesis is impaired in many neurodegenerative diseases, therapeutic approaches that stimulate neurogenesis may have potential to stimulate repair and even recovery, thereby providing innovative, disease-modifying treatments [9][10] . Therefore, LRRK2 inhibitors may have a dual therapeutic role: the first one due to the direct beneficial effect of LRRK2 inhibition and the second one as enhancing adult neurogenesis.…”