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  • Gp induces cell death by

    2021-09-10

    Gp120 induces cell death by apoptotic mechanisms and increases intracellular Ca, and activates messengers related to cell death. Intracellular mechanisms of neuronal damage are mainly a consequence of the activation of the N-methyl-d-aspartate receptor (NMDAR) [2], [5], which induces excitotoxicity caused by oxidative stress and mitochondrial alterations [6], [7]. Neuropathic pain in HIV infection also involves gp120, and gp120 also contributes to hyperalgesia in rodents when administered peripherally [8], [9] or centrally. The mechanism is indirect and depends on effects of gp120 on glial Fmoc-Leu-OPfp and the release of inflammatory cytokines, which are involved in neurological disorders and development of pain [10], [11]. Previous studies have shown that activation of glial cells and macrophages are responsible for the release of inflammatory cytokines, including IL-1β, TNF-α and IL-6 [4], [10], which is of fundamental importance in the induction of hyperalgesia caused by intrathecal administration of gp120. Generation of hyperalgesia involves the activation of NF-κB in the spinal cord, which is associated with nociceptive behavioral changes [11], [12]. Animal studies have demonstrated that a single application of gp120 to the sciatic nerve leads to migration of macrophages, the induction of persistent inflammatory processes and hyperalgesia [8], [13]. This ability of HIV and gp120 to induce in neuronal tissue a chronic inflammatory state may contribute to the development of the depressive symptoms that often affect people with HIV [14]. Drugs with anti-inflammatory properties, which inhibit the signaling pathways of inflammatory cytokines, have been proven to be beneficial in studies that seek new alternatives for the treatment of neurocognitive impairments [10]. A study conducted by our research group with the essential oil of Schinus terebinthifolius and the compound (R)-(+)-limonene has shown that both the oil and the compound possess antidepressant and antihyperalgesic effects in a rat neuropathic pain model [8], [15]. Other evidence suggests that limonene has potent anxiolytic [16], [17], antidepressive [18], [19], antinociceptive [20], immunomodulatory [21] and even anti-inflammatory Fmoc-Leu-OPfp activities [22], [23], [24], [25].
    Materials and methods
    Results
    Discussion The present study demonstrates that oral administration of limonene reduces centrally mediated mechanical hyperalgesia induced by intrathecal administration of gp120, Interleukin-1β (IL-1β), and Tumor Necrosis Factor-α (TNF-α) in mice. The oral administration of limonene decreased the ability of intrathecal injection of gp120 to increase IL-1β and IL-10 levels in serum from peripheral blood. IL-10 is an anti-inflammatory cytokine that reduces inflammation through its ability to block NF-kB activation [33]. IL-10 expression following gp120 administration may limit the inflammatory effects of gp120. The ability of gp120 to induce both IL-1β and IL-10, and of limonene to block the induction of these two cytokines suggests that both cytokines are under similar positive and negative control. To our knowledge, this is the first time that an antihyperalgesic activity of limonene has been shown in gp120 and cytokine models. We observed cytokine expression in serum. Because the injection of gp120 was intrathecal, spinal cord is the likely site of cytokine expression, however this remains to be verified. Furthermore, although oral administration of limonene modulated the expression of SOD and HSP90 analyzed by Western blot, the regulation was distinct from regulation of IL-1β and TNF-α, suggesting that control of these proteins by the inflammatory cytokines takes place by a different mechanism. Patients infected with HIV-1 experience hypersensitivity to pain and neuropathies [4]. Initially, HIV enters cells by binding to the CD4 receptor, an action mediated by the viral surface glycoprotein gp120. The auxiliary co-receptors CCR5 and CXCR4 facilitate this process. After entry, HIV proteins are synthesized to produce new virions and the expression of the new viral proteins is thought to contribute to the generation of pain and other symptoms in HIV patients. Gp120 is the main antigen of HIV involved in the generation of mechanical hyperalgesia when administered in the rat paw [9], sciatic nerve [8] or by a central route [30].