Valproic acid attenuates inflammation in experimental autoimmune neuritis.

Valproic acid (VPA) is a short-chain branched fatty with anti-inflammatory, neuro-protective and axon-remodeling effects. We investigated the effects of VPA in rats in which experimental autoimmune neuritis (EAN) had been induced (EAN rats). VPA (300 mg/kg, intraperitoneally) administration to EAN rats once daily immediately following immunization significantly suppressed mRNA levels of interferon-gamma, tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-4, IL-6 and IL-17 in the lymph nodes of EAN rats. In peripheral blood and sciatic nerves of EAN rats, Foxp3(+) cells were increased but IL-17(+) cells were decreased during VPA treatment. Furthermore, suppressive and therapeutic treatment with VPA greatly attenuated both accumulation of macrophages, T cells and B cells, and demyelination in sciatic nerves, and greatly reduced the severity and duration of EAN. In summary, our data demonstrated that VPA could effectively suppress inflammation in EAN, suggesting that VPA could be a potent candidate for treatment of autoimmune neuropathies.

Mechanical allodynia and spinal up-regulation of P2X4 receptor in experimental autoimmune neuritis rats.

Experimental autoimmune neuritis (EAN) is the animal model of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) that is the most common subtype of Guillain-Barre syndrome (GBS). While neuropathic pain is a common symptom of GBS, its underlying mechanisms remain elusive. Central sensitization, particularly spinal glia (microglia and astrocytes) activation, is important for the initiation and maintenance of neuropathic pain. P2X(4) receptor (P2X(4)R) is an ATP-gated ion channel and its spinal up-regulation has been found to be crucial for the development of neuropathic pain following peripheral nerve injury. The initiation of mechanical allodynia in rat EAN was observed at day 9 before the onset of neurological signs. Maximal level of mechanical allodynia was observed from days 17-19 and then a slow recovery, long after the cessation of typical neurological signs of EAN, until day 37 was observed. Expression of P2X(4)R in lumbar spinal cords was studied by immunohistochemistry. P2X(4)R immunoreactivity (IR) was mainly seen in gray matter, particularly in the dorsal horn. Accumulation of P2X(4)R(+) cells in the lumbar dorsal horn was observed at day 9, reached the maximal level at day 17 and remained elevated until day 37 after immunization. Furthermore, a negative correlation between the density of P2X(4)R(+) cells in the lumbar dorsal horn with mean hind-paw withdrawal threshold in EAN rats was seen, indicating that P2X(4)R might contribute to EAN mechanical allodynia. Double staining revealed that almost all P2X(4)R(+) cells co-expressed CD68, a marker for reactive microglia, but not the astrocyte marker, glial fibrillary acidic protein (GFAP). Our data demonstrate that EAN induces mechanical allodynia and P2X(4)R expression in spinal microglia, suggesting that EAN is a good animal model for neuropathic pain in polyneuropathy and spinal microglia activation might participate in EAN-induced neuropathic pain.

Early attenuation of lesional interleukin-16 up-regulation by dexamethasone and FTY720 in experimental traumatic brain injury.

AIMS: Interleukin-16 (IL16) is an immunomodulatory cytokine, which induces lymphocyte migration, expression of proinflammatory IL1 beta, IL6 and tumour necrosis factor-alpha, and modulates apoptosis. IL16 expression has been observed in several central nervous system diseases and may play a role in promoting inflammatory responses. Inflammation contributes considerably to secondary injury following traumatic brain injury (TBI). The aim of this study was to investigate early IL16 expression following experimental TBI and the effects of dexamethasone and FTY720 on early expression of IL16 in TBI rats. METHODS: Rat TBI was induced using an open-skull weight-drop model. IL16 expression was studied by immunohistochemistry. TBI rats received an intraperitoneal injection of dexamethasone (1 mg/kg in 1 ml saline), FTY720 (1 mg/kg in 1 ml saline) or saline (1 ml) on Day 0 and Day 2 immediately after surgery. RESULTS: Significant up-regulation of IL16 was seen as early as 24 h post TBI. Double-staining experiments, together with morphological classification, revealed a multicellular origin of IL16, including activated microglia/macrophages (about 85%), astrocytes (about 8%), neurones (about 5%) and granulocytes. Following peripheral administration of dexamethasone and FTY720, attenuated numbers of IL16(+) cells were observed on Days 1 and 2 but not on Day 4 post TBI for dexamethasone and on Day 4 but not earlier for FTY720 respectively. CONCLUSIONS: Our observations reveal that dexamethasone and FTY720 have different but complementary effects on reduction of early IL16 expression following TBI.

Lesional expression of the endogenous angiogenesis inhibitor endostatin/collagen XVIII following traumatic brain injury (TBI).

We have analysed the expression of the endogenous angiogenesis inhibitor endostatin/collagen XVIII following stab wound injury and observed a highly significant (p<0.0001) lesional accumulation confined to areas of pan-necrotic injury and developing secondary damage. Maximal cell numbers were detected at Day 14, declining until Day 21 after injury. Further, endostatin/collagen XVIII(+) monocytic cells accumulated in Virchow-Robin spaces where they formed cell clusters. Besides being prevailingly localised to ED1(+) activated microglia/macrophages, endostatin/collagen XVIII expression was also detected by subendothelial surrounding vessels in the lesioned area. Late and prolonged accumulation of endostatin/collagen XVIII(+) microglia/macrophages and increased numbers of endostatin/collagen XVIII(+) subendothelial cells/vessels in areas of vascular pruning and regression, point to a role in the termination of the transient angiogenic response, linked to a "late" inflammatory milieu.

Dexamethasone transiently attenuates up-regulation of endostatin/collagen XVIII following traumatic brain injury.

Endostatin/collagen XVIII is a specific inhibitor of endothelial proliferation and migration in vitro. It has also been shown to have anti-angiogenic activity and tumor growth inhibitory activity in vivo and in vitro. Here we studied expression of endostatin/collagen XVIII in a rat traumatic brain injury (TBI) model, focusing on the early phase. A significant up-regulation of endostatin/collagen XVIII in TBI began as early as 24 h post-TBI. Double-staining experiment revealed that the major resource of endostatin/collagen XVIII(+) cells in our TBI rat model was a subpopulation of reactivated microglia/macrophages. Our data further showed that dexamethasone attenuated up-regulation of endostatin/collagen XVIII expression at days 1 and 2, but not at day 4, post-TBI, indicating that dexamethasone might possess an early and transient influence to the angiogenesis following TBI.

On the metabolism of lipoprotein-X (LP-X).

The characteristic low-density lipoprotein of cholestasis (LP-X) earlier described for humans is found with identical properties in dogs and rats after experimental cholestasis. After ligation of the common bile duct, LP-X may be detected in the plasma within the first 20 hours. A period of marked increase in concentration is followed by decreasing plasma concentrations and LP-X becomes undetectable 7-10 days after ligation of the bile duct in rats. High plasma bile salt concentration may alter the structural integrity of LP-X and may in part be responsible for its disappearance after long-lasting and severe biliary obstruction. Plasma decay curves for isolated LP-X injected intravenously into healthy animals revealed a rapid early fall in concentration followed by a gradual decline. The calculated fractional catabolic rate of LP-X was found to be 0.450 +/- 0.069 for dogs and 1.553 +/- 0.096 for rats corresponding to a mean biological half life of 37.7 +/- 6.4 h or 10.7 +/- 0.6 h, respectively. In vitro LP-X degradation occurs in post-heparin plasma, however, it seems to be too early to speculate on the enzyme activity and on the mode of action responsible for this disappearance.