AbstractBackgroundMany brain areas participate to supraspinal control of nociception. In these regions, few studies have investigated the role of glial cells in supraspinal plasticity and the effect of 7‐day intrathecal nerve growth factor‐like (BB14®, Blueprint Biotech, Milano, Italy) treatment.MethodsIn male Sprague‐Dawley rats, we evaluated by immunohistochemistry the morphological and molecular rearrangement of neuroglial network occurring in several supraspinal brain regions involved in pain processing following spared nerve injury (SNI) of the sciatic nerve. In particular, the medial prefrontal cortex, the amygdala (Amy), the nucleus accumbens (Acb), the thalamus and the periaqueductal gray were analysed.ResultsDespite the modifications occurring in the dorsal horn of spinal cord following SNI, no significant changes in the Iba1 and glial fibrillary acidic protein (GFAP) expression were detected in all the analysed supraspinal regions, except for the Amy, showing a remarkable GFAP increase. Interestingly, neuropathic rats also displayed a significant increase of glial transporters (GTs) in all the supraspinal regions. Finally, the analysis of vesicular glutamate transporter 1 (vGLUT1) and vesicular gamma‐aminobutyric acid (GABA) transporter (vGAT) expression revealed a significant enhancement of glutamatergic/GABAergic ratio in all selected brain regions of SNI animals, except for Acb. Both glial activation in the Amy and alteration of GTs and vGLUT/vGAT levels observed in neuropathic animals were largely reversed by BB14® treatment.ConclusionsAll together, these data strengthen the role of supraspinal neuroglial network plasticity in the establishment of neuropathic pain syndrome. The hallmark is represented by the divergence between glial reaction confined to Amy and the widespread changes in the GT distribution and glutamate/GABA ratio detected in the other supraspinal region.

01 Jan 2012·Biotechnology AdvancesQ1 · ENGINEERING & TECHNOLOGY

BB14, a Nerve Growth Factor (NGF)-like peptide shown to be effective in reducing reactive astrogliosis and restoring synaptic homeostasis in a rat model of peripheral nerve injury

Q1 · ENGINEERING & TECHNOLOGY

Article

Author: Maria Rosaria Bianco ; Lilia Alberghina ; Giovanni Cirillo ; Michele Papa ; Anna Maria Colangelo ; Laura Zaccaro ; Carlo Cavaliere ; Paolo Sarmientos

Peptidomimetics hold a great promise as therapeutic agents for neurodegenerative disorders. We previously described a Nerve Growth Factor (NGF)-like peptide, now named BB14, which was found to act as a strong TrkA agonist and to be effective in the sciatic nerve injury model of neuropathic pain. In this report we present the effects of BB14 in reducing reactive astrocytosis and reverting neuroplastic changes of the glutamate/GABAergic circuitry in the lumbar spinal cord following spared nerve injury (SNI) of the sciatic nerve. Immunohistochemical analysis of spinal cord sections revealed that SNI was associated with increased microglial (Iba1) and astrocytic (GFAP) responses, indicative of reactive gliosis. These changes were paralleled by (i) decreased glial aminoacid transporters (GLT1 and GlyT1) and increased levels of (ii) neuronal glutamate transporter EAAC1, (iii) neuronal vesicular GABA transporter (vGAT) and (iv) the GABAergic neuron marker GAD65/67. A remarkable increase of the Glutamate/GABA ratio and the reduction of glutathione (GSH) levels were also indicative of modifications of glial function in neuroprotection. All these molecular changes were found to be linked to an alteration of endogenous NGF metabolism, as demonstrated by decreased levels of mature NGF, increase of proNGF and increased activity of NGF-degrading methallo-proteinases (MMPs). Biochemical alterations and SNI-related neuropathic behavior, characterized by allodynia and hyperalgesia, were reversed by 7-days i.t. administration of the NGF-like peptide BB14, as well as by increasing endogenous NGF levels by i.t. infusion of GM6001, a MMPs inhibitor. All together, while confirming the correlation between reactive astrogliosis and perturbation of synaptic circuitry in the SNI model of peripheral nerve injury, these data strongly support the beneficial effect of BB14 in reducing reactive astrogliosis and restoring synaptic homeostasis under pathological conditions linked to alteration of NGF availability and signaling, thereby suggesting a potential role of BB14 as a therapeutic agent.

01 Oct 1995·European Journal of Biochemistry

Properties and Functions of a Neuromedin‐B‐Preferring Bombesin Receptor in Brain Microvascular Endothelial Cells

Article

Author: Jean Philippe Breittmayer ; Christian Frelin ; Catherine Van Renterghem ; Eric Feolde ; Paul Vigne

Endothelial cells were isolated from rat brain microvessels and grown in vitro. They expressed a high density of [125I‐Tyr4]bombesin receptors (Bmax= 0.9 pmol/mg protein) with an apparent Kd value of 10nM. The pharmacological profile of inhibition of the specific [125I‐Tyr4]bombesin binding [bombesin = neuromedin B > gastrin releasing peptide (GRP)] was consistent with the presence of a neuromedin‐B‐preferring receptor. Addition of bombesin, neuromedin B and GRP increased the activity of phospholipase C as measured by the production of total inositol phosphates and from intracellular Ca2+ measurements. They increase 86Rb4 uptake by the Na+, K+, 2C1− cotransporter and by a charybdotoxin‐sensitive, Ca2+‐activated K+ channel and 22Na+ uptake by the Na+/H+ exchanger. The pharmacological profiles of activation of phospholipase C., Na+, K+, 2C1 cotransport and Na+/H+ exchange by bombesin‐like peptide were consistent with an involvement of the neuromedin‐B‐preferring receptor characterized in binding experiments. It is suggested that one of the actions of neuromedin B in brain vessels could be to control K+ secretion by the blood/brain barrier.

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Indication	Highest Phase	Country/Location	Organization	Date
Eye Diseases	Preclinical	IT	Blueprint Medicines Corp.	-

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