Sonic hedgehog mediates BDNF-induced neuroprotection against mitochondrial inhibitor 3-nitropropionic acid

doi:10.1016/j.bbrc.2009.04.145

Biochemical and Biophysical Research Communications

Volume 385, Issue 1, 17 July 2009, Pages 112-117

https://doi.org/10.1016/j.bbrc.2009.04.145 Get rights and content

Abstract

Sonic hedgehog (SHH), a morphogen critical for embryogenesis, has also been shown to be neuroprotective. We have recently reported that pretreatment of rat cortical neurons for 8 h with brain-derived neurotrophic factor (BDNF; 100 ng/ml) affords protection against neurotoxicity of 3-nitropropionic acid (3-NP; 2.5 mM for 24 h), a mitochondrial complex II inhibitor. However, whether SHH is involved in BDNF-mediated neuroprotection remains unknown. Herein we tested whether BDNF induces SHH expression and if so, whether BDNF induction of SHH contributes to the observed neuroprotective effects. We found BDNF (100 ng/ml) increased SHH expression at both mRNA and protein levels. BDNF protection against 3-NP was abolished by cyclopamine (CPM; 5 μM), the SHH pathway inhibitor. Preconditioning of cortical neurons with N-terminal fragment of SHH (SHH-N; 0.1–1 ng/ml) was sufficient to confer resistance. These results indicate that BDNF induces SHH expression, which contributes to neuroprotection against 3-NP toxicity in rat cortical neurons.

Section snippets

Materials and methods

Rat cortical culture. Primary neuronal cultures were prepared from cortices of Sprague–Dawley fetal rat brains at embryonic day 18 as previously described [17]. Cells were grown for 7–8 days in vitro to allow regeneration of dendrites before use. All the procedures for preparation of fetal rat cortical cultures were performed humanely in accordance with the guidelines described in the “User Manual of Laboratory Animal Center at National Yang-Ming University”.

Real-time RT-PCR. Total RNA was

BDNF induces SHH expression in rat cortical cultures

To test the hypothesis that SHH is involved in the BDNF-dependent neuroprotective effects, we first determined whether BDNF may up-regulate expression of SHH in rat cortical neurons. Initial selection of BDNF dosage at 100 ng/ml was based on our previous report showing that BDNF at this concentration conferred neuronal resistance against 3-NP toxicity [16]. We found that BDNF (100 ng/ml) increased expression of SHH mRNA at 4–6 h, with the maximal induction at 6 h (3.45 ± 0.49-folds; Fig. 1A).

Discussion

BDNF belongs to the neurotrophin family that may affect neuronal survival and differentiation. SHH is a morphogen important for the embryonic development. Potential correlation between BDNF and SHH is, however, less well studied. One recent study has shown that SHH expression was up-regulated prior to the induction of BDNF mRNA in Schwann cells adjacent to the injured site in an animal model of sciatic nerve injury [21]. Consistent with a causative relationship between the induction of SHH and

Acknowledgments

This study was supported by National Science Council (NSC97-2314-B-010-008MY3 to Ding-I Yang and NSC96-2314-B-182A-101MY3 to Shang-Der Chen), Ministry of Education (95A-C-P30 to Ding-I Yang) and Department of Health, Taipei City Government (97002-62-040 to Ding-I Yang) in Taiwan.

References (24)

Y. Echelard et al.
Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity
Cell
(1993)
J. Alcedo et al.
The Drosophila smoothened gene encodes a seven-pass membrane protein, a putative receptor for the hedgehog signal
Cell
(1996)
C.V. Borlongan et al.
Systemic 3-nitropropionic acid: behavioral deficits and striatal damage in adult rats
Brain Res. Bull.
(1995)
T.C. Ju et al.
Protective effects of S-nitrosoglutathione against neurotoxicity of 3-nitropropionic acid in rat
Neurosci. Lett.
(2004)
T.C. Ju et al.
Protective effects of S-nitrosoglutathione against amyloid beta-peptide neurotoxicity
Free Radic. Biol. Med.
(2005)
K. Tsuboi et al.
Intrastriatal injection of sonic hedgehog reduces behavioral impairment in a rat model of Parkinson’s disease
Exp. Neurol.
(2002)
D.M. Stone et al.
The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog
Nature
(1996)
V. Marigo et al.
Biochemical evidence that patched is the Hedgehog receptor
Nature
(1996)
N.A. Riobo et al.
Pathways of signal transduction employed by vertebrate Hedgehogs
Biochem. J.
(2007)
A.M. Kenney et al.
Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors
Development
(2003)

G. Regl et al.

Activation of the BCL2 promoter in response to Hedgehog/GLI signal transduction is predominantly mediated by GLI2

Cancer Res.

(2004)

C. Leung et al.

Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas

Nature

(2004)

Cited by (42)

7,8-DHF enhances SHH in the hippocampus and striatum during early abstinence but has minor effects on alcohol intake in IA2BC paradigm and abstinence-related anxiety-like behavior in rats
2022, Neuroscience Letters
Citation Excerpt :
In vitro, BDNF regulates expression of SHH and components of its signaling cascade in neurons. BDNF treatment increases SHH expression at both mRNA and protein levels in cultured rat cortical neurons [11]. Moreover, cerebrolysin, a mixture of neurotrophic peptides with BDNF-like properties, induces SHH and its downstream transcriptional factor GLI (glioma-associated oncogene) mRNAs in neural progenitor cells derived from the subventricular zone of the adult rat lateral ventricles [12].
A mimetic of brain-derived neurotrophic factor (BDNF), 7,8-dihydroxyflavone (7,8-DHF), alleviates some aspects of alcohol abstinence after voluntary alcohol intake in rodents. The interaction between BDNF and sonic hedgehog (SHH) was demonstrated in adult brain in some situations, though relationship between BDNF and SHH during alcohol abstinence remains obscure. We aimed to study effect of 7,8-DHF on drinking pattern, anxiety-like behavior and expression of SHH and a downstream transcription factor, GLI, in the limbic brain structures during early abstinence after voluntary ethanol intake.
Male Wistar rats were subjected to intermittent access to 20% ethanol in a two-bottle choice procedure (IA2BC). The animals experienced twenty 24-h sessions of free access to two-bottle choice (water or 20% ethanol) with 24-h withdrawal periods (water only); 7,8-DHF (5 mg/kg, i.p.) was administered one hour prior to each alcohol access session. Anxiety-like behavior was estimated in the open-field (OFT) and elevated plus-maze (EPM) tests on the first and second days of abstinence, respectively. The expression of SHH and GLI was analyzed on the third day after withdrawal in the frontal cortex, hippocampus and striatum.
Repeated measures ANOVA did not show significant main effect of 7,8-DHF injections during IA2BC on ethanol intake and ethanol preference over water. As expected, pair-wise comparisons of OFT and EPM data by Mann-Whitney U test revealed elevated anxiety-like behavior during early abstinence in IA2BC paradigm as compared with control group. When all groups were included in the analysis, Kruskal-Wallis ANOVA did not show significant differences in time spent in the center zone of the OFT and number of entries. However, time spent in the open arms of the EPM but not number of entries differed significantly between the groups studied according to Kruskal-Wallis ANOVA. Factorial ANOVA followed by Tukey’s HSD post hoc test demonstrated significant elevation of SHH protein levels in the hippocampus and striatum but not in the frontal cortex of animals with access to ethanol and administered with 7,8-DHF as compared with respective animals without 7,8-DHF. GLI expression changed only in the hippocampus; its protein level increased in control animals administered 7,8-DHF.
Thus, 7,8-DHF administration during IA2BC procedure induces region-specific levels elevation of SHH in the brain, but does not significantly change drinking pattern and anxiety-like behavior during early abstinence.
Time and region-dependent manner of increased brain derived neurotrophic factor and TrkB in rat brain after binge-like methamphetamine exposure
2020, Neuroscience Letters
Methamphetamine (MA), a synthetic derivate of amphetamine, has become a major drug of abuse worldwide. This study investigated the effect of binge-like MA dosing (4 x 4 mg/kg, s.c., 2 h (h) apart) at a range of different time points (from 2 h to 7 days after treatment) on brain-derived neurotrophic factor (BDNF) levels and its receptors, TrkB and p75^NTR. BDNF levels were significantly increased in the frontal cortex from 2 to 36 h after treatment, returning to normal within 48 h after treatment. In the striatum, BDNF expression was increased at 12 and 24 h after binge-like MA treatment and had returned to normal at 36 h. Increased expression of the TrkB receptor was observed in the frontal cortex at 2, 24 and 48 h after MA treatment and in the striatum at 24 and 48 h after the MA regimen. A significant increase in the p75^NTR receptor was also noted in the striatum but not the frontal cortex, and it was less pronounced than the effect on TrkB receptor expression. These findings show that the binge-like regimen of MA affects expression of BDNF and its receptors, particularly the TrkB receptor, in a time and region dependent manner, and highlights the importance of the frontal cortex and the striatum in the response following MA binge-like dosing.
The protective mechanisms of polydatin in cerebral ischemia
2019, European Journal of Pharmacology
The prevalence of stroke is high in both developing and developed nations. It causes a heavy social and financial burden to the sufferers and their caregivers. Thrombolytic therapy is the only pharmacological treatment available for stroke. However, thrombolytic agents do not provide substantial improvement on long term motor and cognitive disabilities. Thus, there is a need to explore for new compounds that can halt or reverse the deterioration of neurons in the stroke patients’ brain. Polydatin, a precursor of resveratrol, is a natural stilbene commonly found in food. This review article describes how different parameters were altered with ischemic injury and polydatin treatment, why it is important and how it could be beneficial or useful in future studies. Our review of polydatin provides convincing evidence regarding the potential of polydatin to be developed into preventive or therapeutic products for ischemic stroke. Nevertheless, additional studies are necessary in order to properly elucidate the biological mechanisms of polydatin, especially its molecular mechanisms of protection and target proteins, in cerebral ischemia.
Targeting sonic hedgehog signaling in neurological disorders
2017, Neuroscience and Biobehavioral Reviews
Sonic hedgehog (Shh) signaling influences neurogenesis and neural patterning during the development of central nervous system. Dysregulation of Shh signaling in brain leads to neurological disorders like autism spectrum disorder, depression, dementia, stroke, Parkinson’s diseases, Huntington’s disease, locomotor deficit, epilepsy, demyelinating disease, neuropathies as well as brain tumors. The synthesis, processing and transport of Shh ligand as well as the localization of its receptors and signal transduction in the central nervous system has been carefully reviewed. Further, we summarize the regulation of small molecule modulators of Shh pathway with potential in neurological disorders. In conclusion, further studies are warranted to demonstrate the potential of positive and negative regulators of the Shh pathway in neurological disorders.
Applications of bioresorbable polymers in the central nervous system
2017, Bioresorbable Polymers for Biomedical Applications: From Fundamentals to Translational Medicine
Disorders of the CNS can be divided into insults due to ischemia or trauma, or disorders due to neurodegenerative diseases. Spinal cord injury (SCI) is one of the CNS disorders for which biodegradable polymers may be used to develop new therapies. Today there are no effective treatments to reduce the injury in the acute stage, or enhance the regeneration during the months and years after injury. The strategies that can be used to develop new therapies include bridging tissue gaps, replacing lost cells, enhancing regenerative potential, and making the environment permissive to nerve growth. All these strategies can be addressed with the help of biodegradable polymers. The three-dimensional structure of some biomaterials is in itself supportive to growing axons. The polymers can easily be modified using motifs from extracellular matrix molecules to increase cell adhesion, and possibly to add other positive effects to the material. Biomaterial is per se often well suited as carriers for cells. It can also be used to deliver neurotrophic factors that can stimulate regeneration, and incorporate morphogens that can either steer stem cells included in the biomaterial toward phenotypes of cells that have been lost, or exert other effects on the surrounding tissue. The design of biomaterials can thus allow several simultaneous therapeutic targets to be addressed. If an efficient evaluation and comparison of several therapies for SCI can be conducted, biodegradable polymers provide exquisite conditions to combine several treatments to maximize the chances of developing an effective therapy for people with SCI.
Sonic hedgehog promotes neurite outgrowth of cortical neurons under oxidative stress: Involving of mitochondria and energy metabolism
2017, Experimental Cell Research
Oxidative stress has been demonstrated to be involved in the etiology of several neurobiological disorders. Sonic hedgehog (Shh), a secreted glycoprotein factor, has been implicated in promoting several aspects of brain remodeling process. Mitochondria may play an important role in controlling fundamental processes in neuroplasticity. However, little evidence is available about the effect and the potential mechanism of Shh on neurite outgrowth in primary cortical neurons under oxidative stress. Here, we revealed that Shh treatment significantly increased the viability of cortical neurons in a dose-dependent manner, which was damaged by hydrogen peroxide (H₂O₂). Shh alleviated the apoptosis rate of H₂O₂-induced neurons. Shh also increased neuritogenesis injuried by H₂O₂ in primary cortical neurons. Moreover, Shh reduced the generation of reactive oxygen species (ROS), increased the activities of SOD and and decreased the productions of MDA. In addition, Shh protected mitochondrial functions, elevated the cellular ATP levels and amelioratesd the impairment of mitochondrial complex II activities of cortical neurons induced by H₂O₂. In conclusion, all these results suggest that Shh acts as a prosurvival factor playing an essential role to neurite outgrowth of cortical neuron under H₂O₂ -induced oxidative stress, possibly through counteracting ROS release and preventing mitochondrial dysfunction and ATP as well as mitochondrial complex II activities against oxidative stress.

View all citing articles on Scopus

View full text

Sonic hedgehog mediates BDNF-induced neuroprotection against mitochondrial inhibitor 3-nitropropionic acid

Abstract

Section snippets

Materials and methods

BDNF induces SHH expression in rat cortical cultures

Discussion

Acknowledgments

Cell

Cell

Brain Res. Bull.

Neurosci. Lett.

Free Radic. Biol. Med.

Exp. Neurol.

The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog

Nature

Biochemical evidence that patched is the Hedgehog receptor

Nature

Pathways of signal transduction employed by vertebrate Hedgehogs

Biochem. J.

Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors

Development

Activation of the BCL2 promoter in response to Hedgehog/GLI signal transduction is predominantly mediated by GLI2

Cancer Res.

Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas

Nature