phenanthrenes and Brain-Edema

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) 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

The nuclear enzyme poly(ADP-ribose) polymerase (PARP) is activated by oxidative stress and plays a significant role in postischemic brain injury. We assessed the contribution of PARP activation to the blood-brain barrier (BBB) disruption and edema formation after ischemia-reperfusion. In male Wistar rats, global cerebral ischemia was achieved by occluding the carotid arteries and lowering arterial blood pressure for 20 mins. The animals were treated with saline or with the PARP inhibitor N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N, N-dimethylacetamide.HCl (PJ34); (10 mg/kg, i.v.) before ischemia. After 40 mins, 24, and 48 h of reperfusion, the permeability of the cortical BBB was determined after Evans Blue (EB) and Na-fluorescein (NaF) administration. The water content of the brain was also measured. The permeability of the BBB for EB increased after ischemia-reperfusion compared with the nonischemic animals after 24 and 48 h reperfusion but PARP inhibition attenuated this increase at 48 h (nonischemic: 170+/-9, saline: 760+/-95, PJ34: 472+/-61 ng/mg tissue). The extravasation of NaF showed similar changes and PJ34 post-treatment attenuated the permeability increase even at 24 h. PARP inhibition decreased the brain edema seen at 48 h. Because PARP has proinflammatory properties, the neutrophil infiltration of the cortex was determined, which showed lower values after PJ34 treatment. Furthermore, PJ34 treatment decreased the loss of the tight junction protein occludin at 24 and 48 h. The inhibition of PARP activity accompanied by reduced post-ischemic BBB disturbance and decreased edema formation suggests a significant role of this enzyme in the development of cerebral vascular malfunction

Topics: Animals; Blood-Brain Barrier; Blotting, Western; Brain; Brain Edema; Capillary Permeability; Enzyme Activation; Hypoxia-Ischemia, Brain; Intercellular Adhesion Molecule-1; Male; Membrane Proteins; Occludin; Peroxidase; Phenanthrenes; Poly(ADP-ribose) Polymerases; Rats; Rats, Wistar; Reperfusion Injury; Reverse Transcriptase Polymerase Chain Reaction