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Rebekah J Jakel

Publications and source records attributed to Rebekah J Jakel.

5 recordsLinked to original sources
PubMed2005

Induction of the protective antioxidant response element pathway by 6-hydroxydopamine in vivo and in vitro.

Parkinson's disease, a progressive neurodegenerative disorder, is characterized by loss of midbrain dopaminergic neurons. The etiology of sporadic Parkinson's disease is unknown; however, oxidative stress is thought to play a major role in disease pathogenesis. Little is known regarding the transcriptional changes that occur in Parkinson's disease. The antioxidant response element is a cis-acting enhancer sequence that is upstream of many phase II detoxification and antioxidant genes. Here we show that 6-hydroxydopamine, a mitochondrial inhibitor used to model Parkinson's disease, activates the antioxidant response element both in cultured neurons and in the striatum and brainstem of 6-OHDA-lesioned mice. Pretreatment with antioxidants or NMDA receptor antagonists reduced but did not abolish activation. Further induction of this pathway with tert-butylhydroquinone was able to significantly reduce cell death due to 6-OHDA in vitro. These observations indicate that 6-OHDA activates the antioxidant response element through components of oxidative stress, excitotoxicity, and potential structural factors. Further induction of this endogenous defense mechanism may suggest a novel therapeutic venue in Parkinson's disease.

Animals↗
PubMed2005

Nrf2, a multi-organ protector?

NF-E2-related factor 2 (Nrf2) is a basic leucine zipper transcription factor that binds to the promoter sequence "antioxidant responsive element (ARE)" leading to coordinated up-regulation of ARE-driven detoxification and antioxidant genes. Since the expression of a wide array of antioxidant and detoxification genes are positively regulated by the ARE sequence, Nrf2 may serve as a master regulator of the ARE-driven cellular defense system against oxidative stress. In support of this, numerous studies have shown that Nrf2 protects many cell types and organ systems from a broad spectrum of toxic insults and disease pathogenesis. This Nrf2-conferred, multi-organ protection phenomenon raises an interesting question about how a single protein can protect many different organs from various toxic insults. A possible molecular mechanism explaining this phenomenon is that Nrf2 protects many different cell types by coordinately up-regulating classic ARE-driven genes as well as cell type-specific target genes that are required for the defense system of each cell type in its unique environment. This hypothesis is supported by microarray data indicating the protective role of Nrf2 is conveyed through both known ARE-driven genes and novel cell type-specific genes. The widespread nature of Nrf2 may have an important therapeutic potential, allowing prevention of carcinogenesis and neurodegenerative diseases.

Animals↗
PubMed2004

Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2-mediated transcription.

Complex II inhibitors 3-nitropropionic acid (3NP) and malonate cause striatal damage reminiscent of Huntington's disease and have been shown to involve oxidative stress in their pathogenesis. Because nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent transcriptional activation by means of the antioxidant response element is known to coordinate the up-regulation of cytoprotective genes involved in combating oxidative stress, we investigated the significance of Nrf2 in complex II-induced toxicity. We found that Nrf2-deficient cells and Nrf2 knockout mice are significantly more vulnerable to malonate and 3NP and demonstrate increased antioxidant response element (ARE)-regulated transcription mediated by astrocytes. Furthermore, ARE preactivation by means of intrastriatal transplantation of Nrf2-overexpressing astrocytes before lesioning conferred dramatic protection against complex II inhibition. These observations implicate Nrf2 as an essential inducible factor in the protection against complex II inhibitor-mediated neurotoxicity. These data also introduce Nrf2-mediated ARE transcription as a potential target of preventative therapy in neurodegenerative disorders such as Huntington's disease.

Animals↗
PubMed2004

Human neural stem cell transplants improve motor function in a rat model of Huntington's disease.

The present study investigated the neuroanatomical and behavioral effects of human stem cell transplants into the striatum of quinolinic acid (QA)-lesioned rats. Twenty-four rats received unilateral QA (200 nM/microl) injections into the striatum. One week later, rats were transplanted with stem cells derived from human fetal cortex (12 weeks postconception) that were either 1) pretreated in culture media with the differentiating cytokine ciliary neurotrophic factor (CNTF; n = 9) or 2) allowed to grow in culture media alone (n=7). Each rat was injected with a total of 200,000 cells. A third group of rats (n=8) was given a sham injection of vehicle. Rats transplanted with human stem cells performed significantly better over the 8 weeks of testing on the cylinder test compared with those treated with vehicle (P < or = 0.001). Stereological striatal volume analyses performed on Nissl-stained sections revealed that rats transplanted with CNTF-treated neurospheres had a 22% greater striatal volume on the lesioned side compared with those receiving transplants of untreated neurospheres (P = 0.0003) and a 26% greater striatal volume compared with rats injected with vehicle (P < or = 0.0001). Numerous human nuclei-positive cells were visualized in the striatum in both transplantation groups. Grafted cells were also observed in the globus pallidus, entopeduncular nucleus, and substantia nigra pars reticulata, areas of the basal ganglia receiving striatal projections. Some of the human nuclei-positive cells coexpressed glial fibrillary acidic protein and NeuN, suggesting that they had differentiated into neurons and astrocytes. Taken together, these data demonstrate that striatal transplants of human fetal stem cells elicit behavioral and anatomical recovery in a rodent model of Huntington's disease.

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