Recovery From Experimental Parkinsonism by Semaphorin-guided Axonal Growth of Grafted Dopamine Neurons

Abstract

Cell therapy in animal models of Parkinson's disease (PD) is effective after intrastriatal grafting of dopamine (DA) neurons, whereas intranigral transplantation of dopaminergic cells does not cause consistent behavioral recovery. One strategy to promote axonal growth of dopaminergic neurons from the substantia nigra (SN) to the striatum is degradation of inhibitory components such as chondroitin sulphate proteoglycans (CSPG). An alternative is the guidance of DA axons by chemotropic agents. Semaphorins 3A and 3C enhance axonal growth of embryonic stem (ES) cell-derived dopaminergic neurons in vitro, while Semaphorin 3C also attracts them. We asked whether intranigral transplantation of DA neurons, combined with either degradation of CSPG or with grafts of Semaphorin 3-expressing cells, towards the striatum, is effective in establishing a new nigrostriatal dopaminergic pathway in rats with unilateral depletion of DA neurons. We found depolarization-induced DA release in dorsal striatum, DA axonal projections from SN to striatum, and concomitant behavioral improvement in Semaphorin 3-treated animals. These effects were absent in animals that received intranigral transplants combined with Chondroitinase ABC treatment, although partial degradation of CSPG was observed. These results are evidence that Semaphorin 3-directed long-distance axonal growth of dopaminergic neurons, resulting in behavioral improvement, is possible in adult diseased brains.

Nurr1 promotes neurogenesis of dopaminergic neuron and represses inflammatory factors in the transwell coculture system of neural stem cells and microglia

“…Neural stem cells (NSCs) are self‐renewing with multipotency cells and can differentiate into various neural cells, such as astrocytes, oligodendrocytes, and neurons including dopaminergic neurons . Transplantation of dopaminergic cells derived from embryonic stem cells in a rat model of PD has shown that the grafted cells can survive, differentiate, and extend the processes beyond the graft core and establish synaptic contacts with the host striatum . Therefore, NSCs are considered as one of the most promising donor cells for the treatment of PD and other neurodegenerative diseases.…”

Ascending midbrain dopaminergic axons require descending GAD65 axon fascicles for normal pathfinding

“…This could facilitate the development of combination methods involving secreted guidance cues as used recently to elicit axon growth of intranigrally grafted esDA neurons in rats (Diaz-Martinez et al, 2013) along with substrate-anchored proteins to achieve efficient nigrostriatal DA axon growth in Parkinson's disease.…”

Reference tissue models in the assessment of 11C‐DTBZ binding to the VMAT2 in rat striatum: A test‐retest reproducibility study

“…Subjects underwent two 11 C‐DTBZ PET scans (test‐retest) separated by a 2‐month period [12 weeks (test), 20 ± 2 weeks (re‐test)], which is a typical age and period for the evaluation and follow‐up in animal models of PD after experimental treatments (Díaz et al, ; Díaz‐Martínez et al, ; Rodríguez‐Gómez et al, ). A Focus 120 PET scanner (CTI‐Concorde Microsystems LLC, Knoxville, TN) was used for PET data acquisition.…”