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Targeting neural precursors in the adult brain rescues injured dopamine neurons.

ABSTRACT: In Parkinson's disease, multiple cell types in many brain regions are afflicted. As a consequence, a therapeutic strategy that activates a general neuroprotective response may be valuable. We have previously shown that Notch ligands support neural precursor cells in vitro and in vivo. Here we show that neural precursors express the angiopoietin receptor Tie2 and that injections of angiopoietin2 activate precursors in the adult brain. Signaling downstream of Tie2 and the Notch receptor regulate blood vessel formation. In the adult brain, angiopoietin2 and the Notch ligand Dll4 activate neural precursors with opposing effects on the density of blood vessels. A model of Parkinson's disease was used to show that angiopoietin2 and Dll4 rescue injured dopamine neurons with motor behavioral improvement. A combination of growth factors with little impact on the vasculature retains the ability to stimulate neural precursors and protect dopamine neurons. The cellular and pharmacological basis of the neuroprotective effects achieved by these single treatments merits further analysis.

SUBMITTER: Androutsellis-Theotokis A

PROVIDER: S-EPMC2714762 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Targeting neural precursors in the adult brain rescues injured dopamine neurons.

Androutsellis-Theotokis Andreas A Rueger Maria A MA Park Deric M DM Mkhikian Haik H Korb Erica E Poser Steve W SW Walbridge Stuart S Munasinghe Jeeva J Koretsky Alan P AP Lonser Russel R RR McKay Ronald D RD

Proceedings of the National Academy of Sciences of the United States of America 20090723 32

In Parkinson's disease, multiple cell types in many brain regions are afflicted. As a consequence, a therapeutic strategy that activates a general neuroprotective response may be valuable. We have previously shown that Notch ligands support neural precursor cells in vitro and in vivo. Here we show that neural precursors express the angiopoietin receptor Tie2 and that injections of angiopoietin2 activate precursors in the adult brain. Signaling downstream of Tie2 and the Notch receptor regulate b ...[more]

PMID: 19628689

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Project description:BackgroundNo agents that are specifically neuroprotective are currently approved to emergently treat patients with traumatic brain injury (TBI). The histone deacetylase inhibitor, high-dose valproic acid (VPA) has been shown to have cytoprotective potential in models of combined TBI and hemorrhagic shock, but it has not been tested in an isolated TBI model. We hypothesized that VPA, administered after isolated TBI, will penetrate the injured brain, attenuate the lesion size, and activate prosurvival pathways.MethodsYorkshire swine were subjected to severe TBI by cortical impact. One hour later, animals were randomized to VPA treatment (150 mg/kg delivered intravenously for 1 hour; n = 4) or control (saline vehicle; n = 4) groups. Seven hours after injury, animals were sacrificed, and brain lesion size was measured. Mass spectrometry imaging was used to visualize and quantitate brain tissue distribution of VPA. Sequential serum samples were assayed for key biomarkers and subjected to proteomic and pathway analysis.ResultsBrain lesion size was 50% smaller (p = 0.01) in the VPA-treated animals (3,837 ± 948 mm) compared with the controls (1,900 ± 614 mm). Endothelial regions had eightfold higher VPA concentrations than perivascular regions by mass spectrometry imaging, and it readily penetrated the injured brain tissues. Serum glial fibrillary acid protein was significantly lower in the VPA-treated compared with the control animals (p < 0.05). More than 500 proteins were differentially expressed in the brain, and pathway analysis revealed that VPA affected critical modulators of TBI response including calcium signaling pathways, mitochondria metabolism, and biosynthetic machinery.ConclusionValproic acid penetrates injured brain tissues and exerts neuroprotective and prosurvival effects that resulted in a significant reduction in brain lesion size after isolated TBI. Levels of serum biomarkers reflect these changes, which could be useful for monitoring the response of TBI patients during clinical studies.

Project description:Dibutyryl cyclic adenosine monophosphate (dBcAMP) is a cell-permeable synthetic analog of cyclic adenosine monophosphate (cAMP). Although the elevation of cAMP levels was reported to promote the functional recovery in spinal cord injury, its role in neurogenesis or functional recovery after hippocampal injury is unknown. The objective of the study was to investigate the effects of dBcAMP on learning, memory, and hippocampal neurogenesis in the excitotoxically lesioned hippocampus. An excitotoxic lesion was induced in the hippocampi of 4-month-old male BALB/c mice by injecting 0.25 ?g/?l into the lateral ventricles of both sides. The lesioned mice (L) were divided into L+dBcAMP and L+phosphate-buffered saline (PBS) groups. Sham surgery (S) was done by the injection of 1 ?l of sterile saline into the lateral ventricles. The sham surgery mice were divided into S+dBcAMP and S+PBS groups. Mice in the L+dBcAMP and S+dBcAMP groups were treated with dBcAMP for 1 week (i.p., 50 mg/kg), whereas mice in the L+PBS and S+PBS groups were treated with PBS. The mice in all groups were subjected to water maze and passive avoidance tests at the end of the 4th week. Cresyl violet staining and NeuN and doublecortin immunostaining were done to analyze the morphology and neurogenesis. The water maze learning sessions did not show a significant difference in escape latency between the groups, suggesting an unimpaired learning ability of mice in all groups. The L+dBcAMP mice had significantly short entry latency and higher target quadrant time/distance traveled compared to the L+PBS group, suggesting better memory retention. The L+dBcAMP group had a significantly improved memory retention compared to the L+PBS mice during the passive avoidance test. Morphological studies showed significantly greater adult neurons and increased hippocampal neurogenesis in the hippocampus of mice in the L+dBcAMP group compared to those in the L+PBS group. There was no significant difference between the S+dBcAMP and S+PBS groups in the water maze/passive avoidance tests and the number of neurons. In conclusion, dBcAMP protects the hippocampal neuron from degeneration and enhances hippocampal neurogenesis, learning, and memory.

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Targeting neural precursors in the adult brain rescues injured dopamine neurons.

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Targeting neural precursors in the adult brain rescues injured dopamine neurons.

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