Few studies have examined the signaling pathways that contribute to early brain injury after subarachnoid hemorrhage (SAH). Using a rat SAH model, the authors explored the role of vascular ...endothelial growth factor (VEGF) and mitogen-activation protein kinase (MAPK) in early brain injury. Male Sprague-Dawley rats (n = 172) weighing 300 to 350 g were used for the experimental SAH model, which was induced by puncturing the bifurcation of the left anterior cerebral and middle cerebral arteries. The blood–brain barrier (BBB), brain edema, intracranial pressure, and mortality were evaluated at 24 hours after SAH. The phosphorylation of VEGF and different MAPK subgroups (ERK1/2, p38, and JNK) were examined in both the cortex and the major cerebral arteries. Experimental SAH increased intracranial pressure, BBB permeability, and brain edema and produced high mortality. SAH induced phosphorylation of VEGF and MAPKs in the cerebral arteries and, to a lesser degree, in the cortex. PP1, an Src-family kinase inhibitor, reduced BBB permeability, brain edema, and mortality and decreased the phosphorylation of VEGF and MAPKs. The authors conclude that VEGF contributes to early brain injury after SAH by enhancing the activation of the MAPK pathways, and that the inhibition of these pathways might offer new treatment strategies for SAH.
Tissue injury prompts the release of a number of proalgesic molecules that induce acute and chronic pain by sensitizing pain-sensing neurons (nociceptors) to heat and mechanical stimuli. In contrast, ...many proalgesics have no effect on cold sensitivity or can inhibit cold-sensitive neurons and diminish cooling-mediated pain relief (analgesia). Nonetheless, cold pain (allodynia) is prevalent in many inflammatory and neuropathic pain settings, with little known of the mechanisms promoting pain vs. those dampening analgesia. Here, we show that cold allodynia induced by inflammation, nerve injury, and chemotherapeutics is abolished in mice lacking the neurotrophic factor receptor glial cell line-derived neurotrophic factor family of receptors- alpha 3 (GFR alpha 3). Furthermore, established cold allodynia is blocked in animals treated with neutralizing antibodies against the GFR alpha 3 ligand, artemin. In contrast, heat and mechanical pain are unchanged, and results show that, in striking contrast to the redundant mechanisms sensitizing other modalities after an insult, cold allodynia is mediated exclusively by a single molecular pathway, suggesting that artemin-GFR alpha 3 signaling can be targeted to selectively treat cold pain.
Apoptosis in the endothelium of major cerebral arteries may play a role in the initiation and maintenance of cerebral vasospasm after subarachnoid hemorrhage (SAH). We tested the therapeutic effect ...of caspase inhibitors on endothelial apoptosis and on cerebral vasospasm in an established dog double-hemorrhage model. Thirty-one mongrel dogs were divided into five groups: control; SAH; SAH treated with vehicle DMSO; SAH treated with Ac-DEVD-CHO a specific caspase-3 inhibitor; and SAH treated with Z-VAD-FMK a broad caspase inhibitor. The inhibitors (100 μM) were injected into the cisterna magna daily from Day 0 through Day 3. Angiography was performed on Day 0 and Day 7. Histology, TUNEL staining, and immunohistochemistry were conducted on basilar arteries collected on Day 7 after SAH. Positive staining of TUNEL, poly(ADP)-ribose polymerase (PARP), caspase-3, and caspase-8 was observed in the endothelial cells of the spastic arteries. Double fluorescence labeling demonstrated co-localization of TUNEL with caspase-3 and TNFα-receptor-1 (TNFR1). Ac-DEVD-CHO and Z-VAD-FMK prevented endothelial apoptosis and reduced angiographic vasospasm. The mechanism of apoptosis in endothelial cells involves TNFR1 and the caspase-8 and caspase-3 pathways. Caspase inhibitors may have potential in the treatment of cerebral vasospasm.
Mitogen-activated protein kinase (MAPK) has been implicated in cerebral vasospasm after subarachnoid hemorrhage (SAH). This study was conducted to investigate whether Src tyrosine kinase, an upstream ...regulator of MAPK, is involved in cerebral vasospasm.
An established canine double-hemorrhage model was used. Twenty-four dogs were divided into four groups: control, vehicle-treated, Src inhibitor PP2-treated, and Src inhibitor damnacanthal-treated groups. Vehicle (dimethyl sulfoxide), PP2, or damnacanthal was injected daily into the cisterna magna of 18 dogs at 3 to 6 days after induction of SAH. Angiography was performed on Day 0 (the day on which the first blood injection was administered to induce SAH) and on Day 7. Western blot analysis of Src and MAPK activation in basilar arteries (BAs) collected on Day 7 post-SAH was performed. Severe vasospasm was observed in the BAs of vehicle-treated dogs. Mild vasospasm was observed in all dogs treated with Src inhibitors. Phosphorylated Src and MAPK were increased after SAH and activation of these kinases in the BAs was abolished by PP2 and damnacanthal.
The tyrosine kinase Src is an important upstream regulator of MAPK, and inhibition of Src might offer a new therapy in the management of cerebral vasospasm.
We report a modified 4-vessel occlusion (4VO) rat model.
We used a 1-stage anterior approach for making bilateral hemispheric ischemia.
Modified 4VO method decreased cerebral blood flow to 12% to 14% ...of baseline levels.
This modified 4VO method is a minimally invasive, quick, reliable procedure for producing ischemic changes.
Objective: Monitoring cerebrospinal fluid pressure or intracranial pressure (ICP) is crucial in the study of neurosurgical disorders. In the present study, we report a new lumbar method for ...monitoring ICP in rats.
Methods: A PE10 catheter connected to a pressure transducer was placed into the subarachnoid space of L5 through the duramater after laminectomy to record lumbar cerebrospinal fluid pressure (lumbar-ICP). ICP at the cisterna magna (cisterna-ICP) was recorded simultaneously via a catheter in the subarachnoid space at the cisterna magna. Eighteen anesthetized adult male S-D rats were subjected to baseline recording followed by either experimental subarachnoid hemorrhage (SAH) induced by intravascular puncture method or experimental intracerebral hemorrhage (ICH) induced by blood injection with a stereotaxic system.
Results: Baseline lumbar-ICP and cisterna-ICP varied between 6 and 8
mmHg, and respiratory variation could be detected. A similar acute response to SAH was recorded in both the lumbar-ICP and cisterna-ICP in all rats. In rats subjected to SAH, the lumbar catheter continuously and accurately monitored lumbar-ICP, and reliable pressure tracings were obtained for up to 24
h after SAH. However, continued cisterna-ICP monitoring was abandoned in two rats in the cisterna magna method due to obstruction of the catheter by blood clots (hematoma).
Conclusion: This new lumbar-ICP method is simple, safe, easy, and reliable in rats. Continued lumbar-ICP measurements provided monitoring for up to 24
h after experimental manipulation.
Electroconvulsive therapy (ECT) effect upon seizure cessation was studied in five male Wistar rats using a penicillin intracisternal injection model (which did not damage the cranial vault). Animals ...were observed both clinically and electrographically for seizure development. ECT was applied at varying times following onset of seizure, at varying parameters (frequency, pulsewidth, and duration). ECT affected EEG seizure pattern in several different stimulation parameter-dependent ways: (1) modulation to different pattern; (2) increased interictal time; and (3) seizure cessation. Stimulation with higher, sustained current (50 mA) led to changes in seizure amplitude; stimulation at pulses of current led to seizure frequency dimunition, and at certain characteristic pulses "capture" was seen as the EEG activity mimicked the ECT-inducing stimulation pattern. Interictal time was usually increased by sustained, continuous (rather than pulsatile) stimulation. Seizure activity was completely stopped in several instances using parameters of 800 pulses at a frequency of 200 Hz, with 2.56 ms pulsewidth and 50 mA of current (in consecutive iterations for one specimen). No ECT-related adverse effects were noted. Analogous to the heart, pacing or defibrillating the brain using external scalp electrodes may have a role in the control of otherwise intractable seizures.
We analyzed the disorder of water metabolism in a 32 year-old female with chronic hypernatremia. She had meningitis at 4 years, and ventriculo-peritoneal shunt operation at 13 years because of normal ...pressure ydrocephalus. At 14 years hypernatremia of 166mmol/l was initially found and thereafter hypernatremia ranging from 150 to 166mmol/l has been persisted for the last 18 years. Physical and laboratory findings did not show dehydration. Urine volume was 750-1700ml per day and urinary osmolality (Uosm) 446-984mmol/kg, suggesting no urinary concentrating defect. Plasma arginine vasopressin (AVP) levels ranged from 0.4 to 1.2 pmol/l despite hyperosmolality of 298 through 343mmol/kg under ad libitum water drinking. There was no correlation between plasma osmolality (Posm) and plasma AVP levels, but Uosm had a positive correlation with Posm (r=0.545, P<0.05). Hypertonic saline (5% NaCl) infusion after a water load increased Uosm from 377 to 679mmol/kg, and plasma AVP from 0.2 to 1.3pmol/l. There was a positive correlation between Posm and plasma AVP levels in the hypertonic saline test (r=0.612, P<0.05). In contrast, an acute water load (20ml/kg BW) verified the presence of impaired water excretion, as the percent excretion of the water load was only 8.5% and the minimal Uosm was as high as 710mmol/kg. Urinary excretion of aquaporin-2 remained low in concert with plasma AVP levels. No abnormality in pituitary-adrenocortical function was found. These results indicate that marked hypernatremia is derived from partial central diabetes insipidus and elevated threshold of thirst, and that enhanced renal water handling may contribute to maintenance of body water in the present subject.
Rhinogenous retrobulbar optic neuritis is characterized by neuritis secondary to paranasal sinusitis. A case of rhinogenous retrobulbar optic neuritis that was successfully treated by surgery is ...reported. A 40-year-old man complained of progressive right visual disturbance. The clinical course and neurological examination suggested right retrobulbar optic neuritis. CT and MRI scans demonstrated a massive tumor-like lesion near the right optic canal. Fifteen days after the onset, decompression of the right optic nerve was performed using a right pterional approach. After surgery, visual disturbance improved, and after about 1 month, the symptom had disappeared. Operative findings, histological examination and the postoperative course were consistent with the characteristics of rhinogenous retrobulbar optic neuritis. We consider decompression of the optic nerve to be effective for the treatment of rhinogenous retrobulbar optic neuritis.
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