Heat Shock Proteins Alterations in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory and autoimmune disease characterized by the attack of the immune system on the body's healthy joint lining and degeneration of articular structures. This disease involves an increased release of inflammatory mediators in the affected joint that sensitize sensory neurons and create a positive feedback loop to further enhance their release. Among these mediators, the cytokines and neuropeptides are responsible for the crippling pain and the persistent neurogenic inflammation associated with RA. More importantly, specific proteins released either centrally or peripherally have been shown to play opposing roles in the pathogenesis of this disease: an inflammatory role that mediates and increases the severity of inflammatory response and/or an anti-inflammatory and protective role that modulates the process of inflammation. In this review, we will shed light on the neuroimmune function of different members of the heat shock protein (HSPs) family and the complex manifold actions that they exert during the course of RA. Specifically, we will focus our discussion on the duality in the mechanism of action of Hsp27, Hsp60, Hsp70, and Hsp90.

Targeting α-synuclein as a therapeutic strategy for Parkinson's disease.

INTRODUCTION: α-Synuclein, a neuronal protein, plays a central role in the pathophysiology of Parkinson's disease (PD), the second most prevalent neurodegenerative disorder. Cases of PD have increased tremendously over the past decade necessitating the identification of new therapeutic targets to reduce patient morbidity and to improve PD patients' quality of life. AREAS COVERED: The purpose of this article is to provide an update on the role of α-synuclein in fibrils formation and review its role as an effective immunotherapeutic target for PD. The rapidly expanding evidence for the contribution of α-synuclein to the pathogenesis of PD led to the development of antibodies against the C terminus of α-synuclein and other molecules involved in the inflammatory signaling pathways that were found to contribute significantly to initiation and progression of the disease. EXPERT OPINION: The readers will obtain new insights on the mechanisms by which α-synuclein can trigger the development of PD and other related degenerative disorders along with the potential role of active and passive antibodies targeted against specific form of α-synuclein aggregates to clear neurotoxicity, stop the propagation of the prion-like behavior of these oligomers and reverse neuronal degeneration associated with PD.

Role of the Na+-K+-2Cl- cotransporter in the development of capsaicin-induced neurogenic inflammation.

Recent behavioral and electrophysiological studies have attributed an important role to dorsal root reflexes (DRRs) in the initiation and development of neurogenic inflammation produced by intradermal capsaicin (CAP). The DRRs can occur in peptidergic fibers, resulting in peripheral release of neuromediators that produce vasodilation, plasma extravasation and subsequently hyperalgesia and allodynia. In this study, we have evaluated the effect of spinal administration of bumetanide (a blocker of the Na+-K+-2Cl- cotransporter, NKCC) on DRR activity, changes in cutaneous blood flow (vasodilation), hindpaw edema, mechanical allodynia, and hyperalgesia induced by intradermal injection of 1% CAP in Sprague-Dawley rats. Vasodilation was monitored using laser Doppler flowmetry, neurogenic edema was evaluated by measurements of hindpaw volume, and secondary mechanical allodynia and hyperalesia were tested using von Frey filaments (10 and 200 mN) applied to the plantar surface of the paw. Changes in the blood flow were blocked significantly by intrathecal bumetanide at 10 and 100 microM in both pre- and posttreatment studies. Spinal bumetanide at 10 and 100 microM blocked neurogenic edema when it was administered before CAP injection, but only bumetanide at 100 microM administered after CAP injection reduced the paw edema significantly. Furthermore, the administration of bumetanide onto the spinal cord reduced the increment in DRR activity produced by CAP. Finally, both secondary mechanical allodynia and hyperalesia were reduced by bumetanide at 1, 10, and 100 microM. Taken together these results suggest that NKCC is involved in the increases in DRR activity, neurogenic inflammation and hyperalgesia and allodynia induced by intradermal CAP.

Calcitonin gene-related peptide receptor activation produces PKA- and PKC-dependent mechanical hyperalgesia and central sensitization.

Calcitonin gene-related peptide (CGRP), acting through CGRP receptors, produces behavioral signs of mechanical hyperalgesia in rats and sensitization of wide dynamic range (WDR) neurons in the spinal cord dorsal horn. Although involvement of CGRP receptors in central sensitization has been confirmed, the second-messenger systems activated by CGRP receptor stimulation and involved in pain transmission are not clear. This study tested whether the hyperalgesia and sensitizing effects of CGRP receptor activation on WDR neurons are mediated by protein kinase A or C (PKA or PKC) signaling. Intrathecal injection of CGRP in rats produced mechanical hyperalgesia, as shown by paw withdrawal threshold tests. CGRP-induced hyperalgesia was attenuated significantly by the CGRP1 receptor antagonist, CGRP8-37. The effect was also attenuated significantly by a PKA inhibitor (H89) or a PKC inhibitor (chelerythrine chloride). Electrophysiological experiments demonstrated that superfusion of the spinal cord with CGRP-induced sensitization of spinal dorsal horn neurons. The CGRP effect could be blocked by CGRP8-37. Either a PKA or PKC inhibitor (H89 or chelerythrine) also attenuated this effect of CGRP. These results are consistent with the hypothesis that CGRP produces hyperalgesia by a direct action on CGRP1 receptors in the spinal cord dorsal horn and suggest that the effects of CGRP are mediated by both PKA and PKC second-messenger pathways.

NMDA receptors and associated signaling pathways: a role in knee joint blood flow regulation.

Blood flow changes in response to N-methyl-D-aspartate (NMDA) receptor activation were assessed using a laser Doppler flowmeter. Treatment of the joint with NMDA (1 mM; 0.1 ml) resulted in a significant increase in blood flow while the control phosphate buffer (PB) injection (0.1 M; pH 7.4) had no effect. Blocking NMDA receptors with the antagonist MK 801 (0.1 mM) prevented the increase in blood flow observed following NMDA injection, suggesting specificity of action. The NMDA-evoked vasodilation has been shown to be mediated through activation of several intracellular signaling transduction molecules, namely nitric oxide, release of calcitonin gene-related peptide (CGRP) and CAM kinase II. Blocking actions of these molecules with L-NAME (10 mg/ml), CGRP(8-37) (0.01 mM) and KN-93 (1 microM), respectively, prevented the increase in blood flow induced by NMDA in the present study. These results provide new evidence implicating NMDA receptors in knee joint inflammatory responses.

Role of calcitonin gene-related peptide in the sensitization of dorsal horn neurons to mechanical stimulation after intradermal injection of capsaicin.

This study was designed to assess the role of calcitonin gene-related peptide (CGRP) and its receptor in the sensitization of dorsal horn neurons induced by intradermal injection of capsaicin in rats. Extracellular recordings were made from wide dynamic range (WDR) dorsal horn neurons with receptive fields on the hindpaw in the lumbar enlargement of anesthetized rats. The background activity and responses to brushing, pressing, and pinching the skin were assessed. A postsuperfusion or a presuperfusion of CGRP(8-37) paradigm was followed. When tested 30 min after capsaicin injection, there was an increase in background activity and responses to brush, press, and pinch applied to the receptive field. Superfusion of CGRP(8-37) into the spinal cord at 45 min after capsaicin injection significantly reversed the increased background activity and responses to brush, press, and pinch applied to the receptive field. On the other hand, spinal superfusion of CGRP(8-37) prior to capsaicin injection prevented the increased background activity and responses to brush, press, and pinch of WDR neurons that occurred following capsaicin injection in control experiments. A sensitization of spinal dorsal horn neurons could also be induced by superfusion of the spinal cord with CGRP. The effect could be blocked by CGRP(8-37) dose-dependently. Collectively, these results suggest that CGRP and its receptors are involved in the spinal cord central sensitization induced by intradermal injection of capsaicin.

The role of calcitonin gene-related peptide (CGRP) in the generation and maintenance of mechanical allodynia and hyperalgesia in rats after intradermal injection of capsaicin.

This study was designed to assess the role of calcitonin gene-related peptide (CGRP) and its receptor in the generation and maintenance of secondary mechanical allodynia and hyperalgesia induced by intradermal injection of capsaicin in rats. Paw withdrawal responses (PWRs) to von Frey hairs with different bending forces applied on the rat paw were tested in this study. CGRP(8-37), a specific antagonist of CGRP 1 receptors, was delivered through a microdialysis fiber inserted across the dorsal horn. Post- and pretreatment paradigms were followed. When CGRP(8-37) was administered 1h after capsaicin injection, the mechanical allodynia and hyperalgesia were partially reversed in a dose-dependent manner. On the other hand, when rats were treated with CGRP(8-37) prior to capsaicin injection, the PWRs to von Frey applications were significantly reduced as compared to control animals. Collectively, these results suggest that CGRP receptors present in the dorsal horn are involved in the generation and maintenance of nociceptive behaviors associated with cutaneous inflammation.