phenanthrenes and Brain-Injuries

Brain injury resulting from stroke or trauma can be exacerbated by the release of proinflammatory cytokines, proteases, and reactive oxygen species by activated microglia. The microglial activation resulting from brain injury is mediated in part by alarmins, which are signaling molecules released from damaged cells. The nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) has been shown to regulate microglial activation after brain injury, and here we show that signaling effects of the alarmin S100B are regulated by PARP-1. S100B is a protein localized predominantly to astrocytes. Exogenous S100B added to primary microglial cultures induced a rapid change in microglial morphology, upregulation of IL-1β, TNFα, and iNOS gene expression, and release of matrix metalloproteinase 9 and nitric oxide. Most, though not all of these effects were attenuated in PARP-1(-/-) microglia and in wild-type microglia treated with the PARP inhibitor, veliparib. Microglial activation and gene expression changes induced by S100B injected directly into brain were likewise attenuated by PARP-1 inhibition. The anti-inflammatory effects of PARP-1 inhibitors in acutely injured brain may thus be mediated in part through effects on S100B signaling pathways. GLIA 2016;64:1869-1878.

Topics: Alarmins; Animals; Animals, Newborn; Astrocytes; Benzimidazoles; Brain; Brain Injuries; Cells, Cultured; Cytokines; Disease Models, Animal; Gene Expression Regulation; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Nitric Oxide Synthase Type II; Phenanthrenes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Polysaccharides; S100 Calcium Binding Protein beta Subunit

Poly(ADP-ribose) polymerase (PARP) is activated by oxidative stress and plays an important role in traumatic brain injury (TBI). The objective of this study was to investigate whether PARP activation participated in the blood-brain barrier (BBB) disruption and edema formation in a mouse model of controlled cortical impact (CCI). N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide (PJ34) (10 mg/kg), a selective PARP inhibitor, was administered intraperitoneally at 5 min and 8 h after experimental CCI. After 6 h and 24 h of CCI, the permeability of the cortical BBB was determined after Evans Blue administration. The water content of the brain was also measured. Treatment with PJ34 markedly attenuated the permeability of the BBB and decreased the brain edema at 6 h and 24 h after CCI. Our data showed the up-regulation of nuclear factor-κB in cytosolic fractions and nuclear fractions in the injured cortex, and these changes were reversed by PJ34. Moreover, PJ34 significantly lessened the activities of myeloperoxidase and the levels of matrix metalloproteinase-9, enhanced the levels of occludin, laminin, collagen IV and integrin β1, reduced neurological deficits, decreased the contusion volume, and attenuated the necrotic and apoptotic neuronal cell death. These data suggest the protective effects of PJ34 on BBB integrity and cell death during acute TBI.

Topics: Animals; Blood-Brain Barrier; Brain; Brain Edema; Brain Injuries; Capillary Permeability; Cell Death; Disease Models, Animal; Male; Matrix Metalloproteinase 9; Mice, Inbred BALB C; Neurons; Neuroprotective Agents; NF-kappa B; Occludin; Phenanthrenes; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Random Allocation

Traumatic brain injury (TBI) causes neuronal cell death as well as microglial activation and related neurotoxicity that contribute to subsequent neurological dysfunction. Poly (ADP-ribose) polymerase (PARP-1) induces neuronal cell death through activation of caspase-independent mechanisms, including release of apoptosis inducing factor (AIF), and microglial activation. Administration of PJ34, a selective PARP-1 inhibitor, reduced cell death of primary cortical neurons exposed to N-Methyl-N'-Nitro-N-Nitrosoguanidine (MNNG), a potent inducer of AIF-dependent cell death. PJ34 also attenuated lipopolysaccharide and interferon-γ-induced activation of BV2 or primary microglia, limiting NF-κB activity and iNOS expression as well as decreasing generation of reactive oxygen species and TNFα. Systemic administration of PJ34 starting as late as 24 h after controlled cortical impact resulted in improved motor function recovery in mice with TBI. Stereological analysis demonstrated that PJ34 treatment reduced the lesion volume, attenuated neuronal cell loss in the cortex and thalamus, and reduced microglial activation in the TBI cortex. PJ34 treatment did not improve cognitive performance in a Morris water maze test or reduce neuronal cell loss in the hippocampus. Overall, our data indicate that PJ34 has a significant, albeit selective, neuroprotective effect after experimental TBI, and its therapeutic effect may be from multipotential actions on neuronal cell death and neuroinflammatory pathways.

Topics: Animals; Blotting, Western; Brain Injuries; Cell Death; Disease Models, Animal; Enzyme Inhibitors; Male; Mice; Mice, Inbred C57BL; Microglia; Neurons; Neuroprotective Agents; Phenanthrenes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Rats; Rats, Sprague-Dawley; Recovery of Function

Traumatic brain injury (TBI) is characterized by neuroinflammation, brain edema, and cerebral damage leading to impairment of neurobehavioral function. Triptolide (PG-490), a diterpenoid component from Tripterygium wilfordii Hook F., has anti-inflammatory properties. Whether triptolide has neuroprotective functions when treating TBI is unclear. To investigate this possibility, Sprague-Dawley rats were treated with triptolide immediately after TBI had been induced by a controlled cortical impact procedure or after a sham procedure. TBI produced neuroinflammation when measured on day 1 after TBI, induced cerebral damage when measured on day 1 and day 3, and impaired neurobehavioral functioning over a 28-day observation period. Triptolide suppressed TBI-induced increases in contusion volume, cell apoptosis, edema and the levels of various pro-inflammatory mediators in the brain. Thriptolide reversed the TBI-induced decrease in brain levels of anti-inflammatory cytokine interleukin-10. Importantly, triptolide improved neurobehavioral outcomes regarding motor, sensory, reflex and balance function. We conclude that triptolide confers neuroprotection against TBI, at least in part, via its anti-inflammatory activity.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Brain Edema; Brain Injuries; Disease Models, Animal; Diterpenes; Epoxy Compounds; Inflammation Mediators; Male; Neurons; Neuroprotective Agents; Phenanthrenes; Rats; Rats, Sprague-Dawley; Recovery of Function

Several lines of research suggest that estrogens (and estrogenic compounds) are neuroprotective following experimental traumatic brain injury. However, therapeutic use of estrogens in this and other regards remains controversial. Therefore, analysis of estrogen-like compounds without potential problems similar to estrogens seems warranted. (±) Z-Bisdehydrodoisynolic acid (Z-BDDA) is a seco-steroid that has potent estrogenic as well as antioxidant activities in vitro and in vivo. We evaluated the therapeutic potential of Z-BDDA (300μg/0.1cc/100g body weight, sc) to promote the recovery of behavioral function following lateral fluid percussion injury (FPI) to the brain in male rats. Two hours subsequent to FPI, treatment with Z-BDDA began with a bolus subcutaneous (sc) injection followed by booster treatments given 24 and 48h later. Behavioral testing was initiated on the second day after FPI and results of Z-BDDA treatments were compared to treatment with vehicle only and to sham FPI surgery. Z-BDDA effectively enhanced recovery of coordinated limb movement assessed by locomotor placing performance across the duration of the study. Z-BDDA treated animals also performed better on a spatial memory task in the Morris water maze, showing improved learning curves across days of testing. Vestibulomotor function, measured by beam walk performance, appeared to improve in Z-BDDA treated animals, however these results did not reach statistical significance (p>0.05). Following cessation of the behavioral testing, all animals underwent assessments of gross neuroanatomical pathology. Cortical lesion size and cell death analysis with Fluoro-jade B failed to reveal Z-BDDA enhanced neuroprotection. These findings support our hypothesis that Z-BDDA can facilitate behavioral recovery following FPI in adult male rats although the mechanism(s) of these effects remain to be determined.

Topics: Animals; Brain Injuries; Disease Models, Animal; Estrogens; Male; Phenanthrenes; Rats; Rats, Long-Evans; Recovery of Function; Secosteroids

Traumatic brain injury produces peroxynitrite, a powerful oxidant which triggers DNA strand breaks, leading to the activation of poly(ADP-ribose)polymerase-1 (PARP-1). We previously demonstrated that 3-aminobenzamide, a PARP inhibitor, is neuroprotective in a model of traumatic brain injury induced by fluid percussion in rat, suggesting that PARP-1 could be a therapeutic target. In order to confirm this hypothesis, we investigated the effects of PJ34 and INO-1001, two PARP inhibitors from structural classes other than benzamide, on the post-traumatic consequences. Pre- and post-treatments with PJ34 (30 mg/kg/day) and INO-1001 (10 mg/kg/day) decrease the neurological deficit at 3 days post-injury and this deficit is still reduced at 7 days. These neurological recovery-promoting effects are associated with the inhibition of PARP-1 activation caused by trauma, as demonstrated by abolishment of immunostaining of poly(ADP-ribose). Thus, the present work strengthens strongly the concept that PARP-1 inhibition may be a suitable approach for the treatment of brain trauma.

Topics: Animals; Brain; Brain Injuries; Collagen Type XI; Disease Models, Animal; Enzyme Inhibitors; Immunohistochemistry; Indoles; Male; Nerve Degeneration; Neurons; Neuroprotective Agents; Phenanthrenes; Poly (ADP-Ribose) Polymerase-1; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerases; Rats; Rats, Sprague-Dawley; Recovery of Function; Solubility; Treatment Outcome