Peripheral Levels of BDNF and NGF in Primary Headaches

Blandini, Fabio; Rinaldi, Leslie; Tassorelli, Cristina; Sances, Grazia; Motta, M.; Samuele, Alberta; Fancellu, Roberto; Nappi, Giuseppe; Leon, Alberta

doi:10.1111/j.1468-2982.2005.01006.x

Cited by 60 publications

(51 citation statements)

References 38 publications

(76 reference statements)

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“…Our present findings raise some intriguing implications for designing novel approaches to block P2X 3 receptor sensitization, especially since BDNF levels are indeed increased in migraine patients during the acute phase of the pain attacks (56,57). Pharmacological antagonism of CGRP receptors (33,35) may be an effective analgesic protocol as long as BDNF is not released in a CGRP-independent fashion to perpetuate the P2X 3 receptor up-regulation.…”

Section: Molecular Elements Involved In P2x 3 Gene Transcriptionmentioning

confidence: 99%

Mechanisms Mediating the Enhanced Gene Transcription of P2X3 Receptor by Calcitonin Gene-related Peptide in Trigeminal Sensory Neurons

Simonetti

Giniatullin

Fabbretti

2008

Journal of Biological Chemistry

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The molecular mechanisms underlying migraine pain remain unclear and probably require sustained facilitation in pain-sensing P2X 3 receptors gated by extracellular ATP in nociceptive sensory neurons. The major migraine mediator calcitonin generelated peptide (CGRP) is known to sensitize P2X 3 receptors to increase impulse flow to brainstem trigeminal nuclei. This process is mediated via changes in the expression and function of P2X 3 receptors initially through enhanced trafficking and, later, perhaps through augmented synthesis of P2X 3 receptors. To clarify the mechanisms responsible for CGRP-evoked long lasting alterations in P2X 3 receptors, we used as a model mouse trigeminal ganglion neurons in culture. CGRP activated Ca 2؉ -calmodulin-dependent kinase II, which became localized to the perimembrane region and neuronal processes, a phenomenon already apparent after 30 min and accompanied by a parallel increase in cAMP-response element-binding protein (CREB) phosphorylation and nuclear translocation. These effects triggered increased P2X 3 receptor transcription and were prevented by expressing a dominant negative form of CREB. Increased P2X 3 receptor synthesis was partly mediated by endogenous brain-derived neurotrophic factor (BDNF) because of its block by anti-BDNF antibodies and mimicry by exogenous BDNF. Immunocytochemistry experiments indicated distinct subpopulations of BDNF-or CGRP-sensitive trigeminal neurons with only partial overlap. The present data indicate a novel mechanism for enhancing P2X 3 receptor expression and function in trigeminal sensory neurons by CGRP via CREB phosphorylation. BDNF was an intermediate to extend the sensitizing effect of CGRP also to CGRP-insensitive neurons. This combinatorial action could serve as a powerful process to amplify and prolong pain mediated by P2X 3 receptors.Sensitization of sensory neurons represents the key phenomenon for generating chronic pain that remains relatively refractory to standard treatment (1). Current theories predict that chronic pain is brought about by a gain in the expression and function of sensory nociceptors that enhance their signal flow to the brain to ensure the long lasting nature of this process (2). Clarification of the novel gene expression profiles associated to pain should, therefore, be useful to target emerging molecules (and mechanisms) and for designing new analgesics. Previous studies (3) aimed at detecting changes in transcriptome patterns during pain conditions have provided only a limited description of the global alterations because of the complexity of pain pathologies and signal pathways.Migraine is a classical example of chronic, relapsing pain triggered by local release of endogenous pain mediators, such as the neuropeptide calcitonin gene-related peptide (CGRP) 2 (4, 5) that induces long lasting trigeminal neuronal sensitization (6) and novel gene transcription in sensory neurons (7-9). CGRPmediated signals are transduced at the cell membrane by activation of a G-protein-coupled receptor complex (composed b...

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Section: Molecular Elements Involved In P2x 3 Gene Transcriptionmentioning

confidence: 99%

Mechanisms Mediating the Enhanced Gene Transcription of P2X3 Receptor by Calcitonin Gene-related Peptide in Trigeminal Sensory Neurons

Simonetti

Giniatullin

Fabbretti

2008

Journal of Biological Chemistry

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“…It is well known that NGF has an inflammatory role and its increase is directly related to inflammation and diseases of the immune system (4,6,22), probably due to the direct action of NGF on mast cells and sensory neurones, as proposed by Woolf and Ma (19). Interestingly, dura mater cells contain high levels of NGF and TrKC, and moderate levels of BDNF and NT-4, suggesting that NGF is essential in preserving the integrity of the mast cell/nerve unit (7).…”

Section: Discussionmentioning

confidence: 99%

“…Peripheral noxious stimuli, such as trauma or inflammation, up-regulate NGF in the affected tissue, as well as BDNF in the sensory ganglia. However, while NGF contributes specifically to inflammation and neuropathic pain inducing the sensitization of peripheral nociceptors, BDNF released within the central nervous system acts as a pain modulator contributing to the central sensitization, probably via the activation of NMDA receptors (22).…”

Section: Discussionmentioning

confidence: 99%

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Immunohistochemical profile of neurotrophins in human cranial dura mater and meningiomas

et al. 2009

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Abstract. The immunohistochemical profile of neurotrophins and their receptors in the human cranial dura mater was studied by examining certain dural zones in specimens harvested from different regions (frontal, temporal, parietal and occipital). Dural specimens were obtained during neurosurgical operations performed in ten patients for surgical treatment of intracranial lesions (meningiomas, traumas, gliomas, vascular malformations). The dural fragments were taken from the area of the craniotomy at least 8 cm from the lesion as well as from the area in which the meningioma had its dural attachment. Immunohistochemical characterization and distribution of neurotrophins, with their receptors, were analyzed. The concrete role played by these neurotrophic factors in general regulation, vascular permeability, algic responsivity and release of locally active substances in the human dura mater is still controversial. Our study revealed a general structural alteration of dural tissue due to the invasivity of meningiomatous lesions, together with an improved expression of brain derived neurotrophic factor (BDNF) in highly proliferating neoplastic cells and an evident production of nerve growth factor (NGF) in inflammatory cells, suggesting that BDNF has a role in supporting the proliferation rate of neoplastic cells, while NGF is involved in the activation of a chronic inflammatory response in neoplastic areas. IntroductionMeningiomas are the most common benign intracranial tumors, but some meningiomas show malignancy with invasion into the surrounding structures, as well as a high recurrence rate and extracranial metastases (1). Meningiomas arise from arachnoidal cells, most of which lie in close proximity to the venous sinuses: in fact, this is the most common site for meningioma formation. They are most frequently attached to the dura mater over the superior parasagittal surface of the frontal and parietal lobes, along the sphenoid ridge, in the olfactory grooves, the Sylvian region, superior cerebellum along the falx cerebri, cerebellopontine angle and spinal cord. The tumor is usually well-circumscribed, with the base lying on the dura mater.Histologically, the cells are relatively uniform, with a tendency to form highly-circumscribed whorls and to generally disrupt the distribution and the structure of collagen fibers (main component of dural tissue) and to originate 'psammoma bodies' (laminated concretions) which can calcify and are often strongly vascularized.The remarkable proliferation rate and vascularisation which determine a rapid replacement of normal dural tissue by the neoplastic cells, is regulated by several different growth factors, such as NGF related to an increased activation of the inflammatory cells at the beginning of the neoplastic invasion and BDNF, involved in the increased activation of the tumoral cells.Neurotrophins (NTs), also known as neurotrophic factors, constitute a family of dimeric proteins working as polypeptidic growth factors and acting like extracellular ligands. NTs, including ...

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“…Reduced BDNF and NGF platelet levels have been described in patients with migraine and chronic daily headache (CDH) 5 . BDNF was shown to be increased during migraine and cluster headache attacks 6,7 .…”

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confidence: 99%

Neurotrophic factors in tension-type headache

Domingues

Duarte

Rocha

et al. 2015

Arq. Neuro-Psiquiatr.

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Tension-type headache (TTH) is the most prevalent headache and is associated with a high socioeconomical impact 1 . It has been suggested that episodic TTH (ETTH) is mainly due to peripheral mechanisms such as muscle tenderness. Central mechanisms leading to reduced pain threshold and sensitization in the trigeminal nucleus, thalamus, or somatosensory cortex are probably related with chronic TTH (CTTH) 2 . However, the precise mechanisms determining ETTH and the conversion of ETTH to CTTH remain largely unknown.Neurotrophic factors (NF) are a unique group of polypeptides responsible for neuron survival, axon growth, dendrite prunning, and the expression of essential proteins for the neuronal functioning. NF are classified in different families according to functional and structural characteristics, such as the glial cell line-derived neurotrophic factor (GNDF) family and the neurotrophin super-family that includes the brainderived neurotrophic factor (BDNF), the nerve-growth factor (NGF), the neurotrophin-3 (NT-3), and the neurotrophin-4/5 (NT-4/5) 3 . NF may play a role in nociception by regulating peripheral sensitivity of nociceptors and by modulating the central processing of nociceptive information 4 . Considering that peripheral nociceptors and central processing of nociceptive information are both potentially involved in the pathophysiology of TTH, it is reasonable to hypothetize that NF may be involved in TTH pathogenesis.The association between NF and primary headaches has already been investigated. Reduced BDNF and NGF platelet levels have been described in patients with migraine and chronic daily headache (CDH) 5 . BDNF was shown to be increased during migraine and cluster headache attacks 6,7 . Increased cerebrospinal fluid (CSF) levels of NGF and BDNF, ABSTRACTNeurotrophic factors (NF) are involved in pain regulation and a few studies have suggested that they may play a pathophysiological role in primary headaches. The aim of this study was to investigate NF levels in patients with tension type headache (TTH). We carried out a cross sectional study including 48 TTH patients and 48 age and gender matched controls. Beck Depression and Anxiety Inventories, and Headache Impact Test were recorded. Serum levels of NF were determined by ELISA. There were not significant differences between NF levels between TTH patients and controls. Patients with chronic and episodic TTH had not significant differences in NF levels. The presence of headache at the time of evaluation did not significantly alter the levels of NF. Depression and anxiety scores as well as headache impact did not correlate with NF levels. Our study suggest that the serum levels of NF are not altered in TTH.Keywords: tension-type headache, neurotrophic factors, depression, anxiety. RESUMOOs fatores neurotróficos (FN) participam da regulação da dor e podem ter um papel na fisiopatologia das cefaleias peimárias. O objetivo do presente estudo foi avaliar os níveis séricos de FN em pacientes com cefaleia do tipo tensional (CTT). Foi realizado cort...

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Peripheral Levels of BDNF and NGF in Primary Headaches

Cited by 60 publications

References 38 publications

Mechanisms Mediating the Enhanced Gene Transcription of P2X3 Receptor by Calcitonin Gene-related Peptide in Trigeminal Sensory Neurons

Mechanisms Mediating the Enhanced Gene Transcription of P2X3 Receptor by Calcitonin Gene-related Peptide in Trigeminal Sensory Neurons

Immunohistochemical profile of neurotrophins in human cranial dura mater and meningiomas

Neurotrophic factors in tension-type headache

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