Recent studies indicate that transplanted neural stem/progenitor cells (NSPs) can interact with the environment of the central nervous system and stimulate protection and regeneration of host cells exposed to oxidative stress. Here, a set of animals grafted with NSPs and treated with 3-nitropropionic acid (3-NP) exhibited reduced behavioral symptoms and less severe damage of striatal cytoarchitecture than sham transplanted controls including better survival of neurons. Sites of tissue sparing correlated with the distribution pattern of donor cells in the host brain. To investigate the cellular and molecular bases of this phenomenon, we treated cocultures of NSPs and primary neural cell cultures with 3-NP to induce oxidative stress and to study NSP-dependent activation of antioxidant mechanisms and cell survival. Proactive presence of NSPs significantly improved cell viability by interfering with production of free radicals and increasing the expression of neuroprotective factors. This process was accompanied by elevated expression of ciliary neurotrophic factor (CNTF) and vascular endothelial growth factor (VEGF) in a network of NSPs and local astrocytes. Intriguingly, both in vitro and in vivo, enhanced growth factor secretion stimulated a robust upregulation of the antioxidant enzyme superoxide dismutase 2 (SOD2) in neurons and resulted in their improved survival. Our findings thus reveal a so far unrecognized mechanism of interaction between NSPs and surrounding cells accompanying neuroprotection: through mutual, NSP-triggered stimulation of growth factor production and activation of antioxidant mechanisms, cellular networks may shield the local environment from the arriving impact of oxidative stress.
In addition to alleviating depression, long-term adaptive changes induced by antidepressants may regulate neural plasticity in the diseased brain, providing symptomatic and disease-modifying effects in Parkinson's disease. The present study investigated whether chronic treatment with a frequently prescribed tricyclic antidepressant was neuroprotective in a 6-hydroxydopamine (6-OHDA) rat model of parkinsonism. In lesioned animals, chronic amitriptyline (AMI; 5 mg/kg) treatment resulted in a significant sparing of tyrosine hydroxylase-immunoreactive (THir) neurons in the substantia nigra pars compacta (SNpc) compared with saline treatment. Additionally, striatal fibers were preserved and functional motor deficits were attenuated. Although 6-OHDA lesions did not induce anhedonia in our model, the dose of AMI utilized had antidepressant activity as demonstrated by reduced immobility. Recent in vitro and in vivo data provide evidence that trophic factors such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) may be key mediators of the therapeutic response to antidepressants. Therefore, we investigated whether AMI mediates changes in these specific trophic factors in the intact and degenerating nigrostriatal system. Chronic AMI treatment mediates an increase in nigral BDNF both before and during ongoing degeneration, suggesting it may contribute to neuroprotection observed in vivo. However, over time, AMI reduced BDNF levels in the striatum, indicating tricyclic therapy differentially regulates trophic factors within the nigrostriatal system. Combined, these results suggest that AMI treatment attenuates dopamine neuron loss and elicits significant trophic changes relevant to dopamine neuron survival.
Here, we present our preliminary data showing that neural stem cells (NSCs) can prevent the degeneration of striatal neurons when transplanted into the CNS prior to intoxication with 3-nitropropionic acid (3-NP). In the adult CNS, the number of NSCs, a major source of neural cell populations and plasticity-modulating factors, is relatively low if compared to that of the developing brain. This, together with the adult growth-inhibitory environment, limits its regenerative capacity. Our recent observation has shown that grafted NSCs may rescue/protect neurons in the chronically impaired mesostriatal system. On the basis of this study and because we were also intrigued by our recent observations regarding the rescue/protective role of NSCs in vitro, we decided to test the hypothesis that grafted NSCs can also be deposited preventively in the CNS (and perhaps join the pool of endogenous NSCs of the intact host brain) for later buffering and maintenance of homeostasis when the host is exposed to oxidative stress.
The expression of soluble growth and survival promoting factors by neural precursor cells (NPCs) is suggested to be a prominent mechanism underlying the protective and regenerative effects of these cells after transplantation. Nevertheless, how and to what extent specific NPC-expressed factors contribute to therapeutic effects is not well understood. Using RNA silencing, the current study investigated the roles of two donor NPC molecules, namely glial cell-line derived neurotrophic factor (GDNF) and sonic hedgehog (SHH), in the protection of substantia nigra dopamine neurons in rats treated with 6-hydroxydopamine (6-OHDA). Analyses indicate that as opposed to the knock-down of GDNF, SHH inhibition caused a profound decline in nigrostriatal neuroprotection. Further, SHH silencing also curbed endogenous neurogenesis and the migration of host brdU+/dcx+ neural precursors into the striatum, which was present in the animals receiving control or GDNF silenced NPCs. A change in graft phenotype, mainly reflected by a reduced proportion of undifferentiated nestin+ cells, as well as a significantly greater host microglial activity, suggested an important role for these processes in the attenuation of neuroprotection and neurogenesis upon SHH silencing. Overall these studies reveal core mechanisms fundamental to grafted NPC-based therapeutic effects, and delineate the particular contributions of two graft-expressed molecules, SHH and GDNF, in mediating midbrain dopamine neuron protection, and host plasticity after NPC transplantation.
The discovery of biomarkers for Parkinson’s disease (PD) is challenging due to the heterogeneous nature of this disorder, and a poor correlation between the underlying pathology and the clinically expressed phenotype. An ideal biomarker would inform on PD-relevant pathological changes via an easily assayed biological characteristic, which reliably tracks clinical symptoms. Human dermal (skin) fibroblasts are accessible peripheral cells that constitute a patient-specific system, which potentially recapitulates the PD chronological and epigenetic aging history. Here, we compared primary skin fibroblasts obtained from individuals diagnosed with late-onset sporadic PD, and healthy age-matched controls. These fibroblasts were studied from fundamental viewpoints of growth and morphology, as well as redox, mitochondrial, and autophagic function. It was observed that fibroblasts from PD subjects had higher growth rates, and appeared distinctly different in terms of morphology and spatial organization in culture, compared to control cells. It was also found that the PD fibroblasts exhibited significantly compromised mitochondrial structure and function when assessed via morphological and oxidative phosphorylation assays. Additionally, a striking increase in baseline macroautophagy levels was seen in cells from PD subjects. Exposure of the skin fibroblasts to physiologically relevant stress, specifically ultraviolet irradiation (UVA), further exaggerated the autophagic dysfunction in the PD cells. Moreover, the PD fibroblasts accumulated higher levels of reactive oxygen species (ROS) coupled with lower cell viability upon UVA treatment. In essence, these studies highlight primary skin fibroblasts as a patient-relevant model that captures fundamental PD molecular mechanisms, and supports their potential utility to develop diagnostic and prognostic biomarkers for the disease.