RESUMO
While effective antiretroviral treatment makes human immunodeficiency virus (HIV)-related death decreased dramatically, neuropathic pain becomes one of the most common complications in patients with HIV/acquired immunodeficiency syndrome (AIDS). The exact mechanisms of HIV-related neuropathic pain are not well understood yet, and no effective therapy is for HIV-pain. Evidence has shown that proinflammatory factors (e.g., tumor necrosis factor alpha (TNFα)) released from glia, are critical to contributing to chronic pain. Preclinical studies have demonstrated that non-replicating herpes simplex virus (HSV)-based vector expressing human enkephalin reduces inflammatory pain, neuropathic pain, or cancer pain in animal models. In this review, we describe recent advances in the use of HSV-based gene transfer for the treatment of HIV pain, with a special focus on the use of HSV-mediated soluble TNF receptor I (neutralizing TNFα in function) in HIV neuropathic pain model.
RESUMO
PURPOSE: The aim of this clinical trial was to investigate changes in stroke volume variability (SVV) and left ventricular end-diastolic volume (LVEDV) after a fluid bolus of crystalloid or colloid using real-time three-dimensional transesophageal echocardiography (3D-TEE) and the Vigileo-FloTrac™ system. MATERIALS AND METHODS: After obtaining Institutional Review Board approval, and informed consent from the research participants, 22 patients undergoing scheduled peripheral vascular bypass surgery were enrolled in the study. The patients were randomly assigned to receive 500 mL of hydroxyethyl starch (HES; HES group, n=11) or normal saline (Saline group, n=11) for fluid replacement therapy. SVV was measured using the Vigileo-FloTrac system. LVEDV, stroke volume, and cardiac output were measured by 3D-TEE. The measurements were performed over 30 minutes before and after the fluid bolus in both groups. RESULTS: SVV significantly decreased after fluid bolus in both groups (HES group, 14.7%±2.6% to 6.9%±2.7%, P<0.001; Saline group, 14.3%±3.9% to 8.8%±3.1%, P<0.001). LVEDV significantly increased after fluid loading in the HES group (87.1±24.0 mL to 99.9±27.2 mL, P<0.001), whereas no significant change was detected in the Saline group (88.8±17.3 mL to 91.4±17.6 mL, P>0.05). Stroke volume significantly increased after infusion in the HES group (50.6±12.5 mL to 61.6±19.1 mL, P<0.01) but not in the Saline group (51.6±13.4 mL to 54.1±12.8 mL, P>0.05). Cardiac output measured by 3D-TEE significantly increased in the HES group (3.5±1.1 L/min to 3.9±1.3 L/min, P<0.05), whereas no significant change was seen in the Saline group (3.4±1.1 L/min to 3.3±1.0 L/min, P>0.05). CONCLUSION: Administration of colloid and crystalloid induced similar responses in SVV. A higher plasma-expanding effect of HES compared to normal saline was demonstrated by the significant increase in LVEDV.
RESUMO
BACKGROUND: Human immunodeficiency virus (HIV)-related painful sensory neuropathies primarily consist of the HIV infection-related distal sensory polyneuropathy and antiretroviral toxic neuropathies. Pharmacotherapy provides only partial relief of pain in patients with HIV/acquired immune deficiency syndrome because little is known about the exact neuropathological mechanisms for HIV-associated neuropathic pain (NP). Hypofunction of γ-aminobutyric acid (GABA) GABAergic inhibitory mechanisms has been reported after peripheral nerve injury. In this study, we tested the hypothesis that HIV gp120 combined with antiretroviral therapy reduces spinal GABAergic inhibitory tone and that restoration of GABAergic inhibitory tone will reduce HIV-related NP in a rat model. METHODS: The application of recombinant HIV-1 envelope protein gp120 into the sciatic nerve plus systemic ddC (one antiretroviral drug) induced mechanical allodynia. The hind paws of rats were inoculated with replication-defective herpes simplex virus (HSV) vectors genetically encoding gad1 gene to express glutamic acid decarboxylase 67 (GAD67), an enzyme that catalyzes the decarboxylation of glutamate to GABA. Mechanical threshold was tested using von Frey filaments before and after treatments with the vectors. The expression of GAD67 in both the lumbar spinal cord and the L4-5 dorsal root ganglia was examined using western blots. The expression of mitochondrial superoxide in the spinal dorsal horn was examined using MitoSox imaging. The immunoreactivity of spinal GABA, pCREB, and pC/EBPß was tested using immunohistochemistry. RESULTS: In the gp120 with ddC-induced neuropathic pain model, GAD67 expression mediated by the HSV vector caused an elevation of mechanical threshold that was apparent on day 3 after vector inoculation. The antiallodynic effect of the single HSV vector inoculation expressing GAD67 lasted >28 days. The area under the time-effect curves in the HSV vector expressing GAD67 was increased compared with that in the control vectors (P = 0.0005). Intrathecal GABA-A/B agonists elevated mechanical threshold in the pain model. The HSV vectors expressing GAD67 reversed the lowered GABA immunoreactivity in the spinal dorsal horn in the neuropathic rats. HSV vectors expressing GAD67 in the neuropathic rats reversed the increased signals of mitochondrial superoxide in the spinal dorsal horn. The vectors expressing GAD67 reversed the upregulated immunoreactivity expression of pCREB and pC/EBPß in the spinal dorsal horn in rats exhibiting NP. CONCLUSIONS: Based on our results, we suggest that GAD67 mediated by HSV vectors acting through the suppression of mitochondrial reactive oxygen species and transcriptional factors in the spinal cord decreases pain in the HIV-related neuropathic pain model, providing preclinical evidence for gene therapy applications in patients with HIV-related pain states.
