Loma Linda University

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John Zhang, MD, PhD
Vice Chair, Basic Sciences, Physiology Division
School of Medicine
Professor, Basic Sciences
School of Medicine
Professor, Anesthesiology
School of Medicine
Professor, Neurology
School of Medicine
Professor, Neurosurgery
School of Medicine
Professor, Nursing - Graduate
School of Nursing
Professor, Pathology and Human Anatomy
School of Medicine
Publications    Scholarly Journals--Published
  • .Hyong A, Jadhav V, Lee S, Tong W, Rowe J, Zhang JH, Tang J.Rosiglitazone, a PPAR gamma agonist, attenuates inflammation after surgical brain injury in rodents. Brain Res. 2008 Jun 18;1215:218-24. Epub 2008 Apr 22. ( 6/2008 )
  • Jadhav V, Zhang JH.Surgical brain injury: prevention is better than cure. Front Biosci. 2008 May 1;13:3793-7 ( 5/2008 )
  • Ayer RE, Sugawara T, Chen W, Tong W, Zhang JH.Melatonin decreases mortality following severe subarachnoid hemorrhage. J Pineal Res. 2008 Mar;44(2):197-204.PMID: 18289172 [PubMed - indexed for MEDLINE] ( 3/2008 )
  • Ostrowski RP, Graupner G, Titova E, Zhang J, Chiu J, Dach N, Corleone D, Tang J, Zhang JH. The hyperbaric oxygen preconditioning-induced brain protection is mediated by a reduction of early apoptosis after transient global cerebral ischemia. Neurobiol Dis. 2008 Jan;29(1):1-13. Epub 2007 Jul 28. ( 1/2008 )
  • Sugawara T, Ayer R, Jadhav V, Zhang JH.A new grading system evaluating bleeding scale in filament perforation subarachnoid hemorrhage rat model. J Neurosci Methods. 2008 Jan 30;167(2):327-34. Epub 2007 Aug 12. ( 1/2008 )
  • Armin S, Colohan A, Zhang JH:  Vasospasm in Traumatic Brain Injury (Review). The 9th International Conference on Cerebral Vasospasm. Acta Neurochirurgica Supplement 2007 (Review) ( 12/2007 )
  • Ayer RE, Zhang JH: , J.H. Oxidative Stress in SAH: Significance in Acute Brain Injury and Vasospasm. The 9th International Conference on Cerebral Vasospasm. Acta Neurochirurgica Supplement 2007 (Review) ( 12/2007 )
  • Sugawara, t, Ayer R, Zhang JH:  Role of Statins in Cerebral Vasospasm. The 9th International Conference on Cerebral Vasospasm. Acta Neurochirurgica Supplement 2007 (Review) ( 12/2007 )
  • Ayer R, Zhang JH: Comment on: Neural Stem Cell Markers, Nestin and Musashi Proteins, in Progression of Human Glioma: Correlation of Nestin with Prognosis of Patient Survival. Surgical Neurology 68: 143-144, Dec 2007 (Editorial) ( 12/2007 )
  • Yamaguchi M, Jadhav V, Obenaus A, Colohan A, Zhang JH.Matrix metalloproteinase inhibition attenuates brain edema in an in vivo model of surgically-induced brain injury. Neurosurgery. 2007 Nov;61(5):1067-75; discussion 1075-6. ( 11/2007 )
  •  Titova E, Ostrowski RP, Sowers LC, Zhang JH, Tang J. Effects of apocynin and ethanol on intracerebral haemorrhage-induced brain injury in rats.Clin Exp Pharmacol Physiol. 2007 Sep;34(9):845-50. PMID: 17645627 ( 9/2007 )
  • Editor, Special Issue, Frontiers of Neurosurgery Research. Front  Biosci September 2007 ( 9/2007 )
  • Zhou D, Matchett G, Jadhav V,  Dach N, Zhang JH: The Effect of 2-Methoxyestradiol, a HIF-1α Inhibitor, in Global Cerebral Ischemia in Rats. Neurological Research Aug 22, 2007 ( 8/2007 )
  • Liu S, Tang J, Ostrowski R, Titova E, Monroe C, Chen W, Lo R, Martin R, Zhang JH: Oxidative Stress after SAH in gp91phox Knockout Mice. Can J NeurolSci 34(3): 356-361, Aug 2007 ( 8/2007 )
  • R. Ostrowski, G. Graupner, E. Titova, J. Zhang, J. Chiu, N. Dach, D. Corleone, J. Tang, J. Zhang. The Hyperbaric Oxygen Preconditioning-Induced Brain Protection is mediated by A Reduction of Early Apoptosis after Transient Global Cerebral Ischemia. Neurobiology of Disease 29(1): 1-13, Jul 28, 2007 ( 7/2007 )
  • Titova E, Ostrowski R, Zhang JH, Tang J:  Experimental Models of SAH for Studies of Cerebral Vasospasm. Neurological Research July 2007 (Review) ( 7/2007 )
  • Huang ZX, Kang ZM, Gu GJ, Peng GN, Yun L, Tao HY, Xu WG, Sun XJ, Zhang JH.. "Therapeutic effects of hyperbaric oxygen in a rat model of endothelin-1-induced focal cerebral ischemia.." Brain Res 1153. (2007): 204-213. ( 6/2007 )
    It has been established that hyperbaric oxygen (HBO) treatment reduces brain edema, decreases infarct volume, contributes to neurological functional recovery and suppresses apoptosis in suture-induced focal cerebral ischemic animal models. In the present study, we evaluated the therapeutic effect of HBO in an endothelin-1-induced focal cerebral ischemia in rats and explored the associated mechanisms of HBO-induced brain protection. One hundred twenty male Sprague-Dawley rats (280 to 320 g) were randomly assigned to sham, focal cerebral ischemia and focal cerebral ischemia treated with HBO groups. Brain water content, neurological function, morphology and molecular biological markers were assessed. HBO (100% O2, 2.5 atmosphere absolute for 2 h) was initiated at 1 h after focal cerebral ischemia. Rats were killed at 24 h to harvest tissues for Western blot or for histology. In HBO-treated animals, an enhanced ratio of Bcl-2 and Bax and a reduced expression of hypoxia-inducible factor-1alpha (HIF-1alpha) in the hippocampus after focal cerebral ischemia were observed. These results indicate that HBO provides brain protection that is probably associated with the inhibition of HIF-1alpha and the elevation of Bcl-2.
  • Yatsushige H, Ostrowski R, Tsubokawa T, Colohan A, Zhang JH. "Role of c-Jun N-terminal kinase in early brain injury after SAH." J Neurosci Res 85.7 (2007): 1436-1448. ( 5/2007 )
    The c-Jun N-terminal kinase (JNK) is induced by cerebral ischemia and injurious blood components acutely after subarachnoid hemorrhage (SAH). We hypothesized that inhibition of JNK will prevent damage to the neurovascular unit in the early brain injury period after SAH. Ninety-nine male SD rats (300-350 g) were randomly assigned to sham, SAH, and SAH treated with JNK inhibitor groups. SAH was induced by endovascular perforation. The JNK inhibitor SP600125 was administered intraperitoneally at 1 hr before and 6 hr after SAH. At 24 hr after SAH, we observed increased phosphorylation of JNK and c-Jun. Signs of neurovascular damage were observed in the hemorrhagic brains; these included the increases of aquaporin (AQP)-1 expression and brain water content as well as enhanced matrix metalloproteinase (MMP)-9 activity, vascular collagen IV loss, increased VEGF tissue level, and Evans blue extravasation. The appearances of cleaved caspase-3 expression, TUNEL-positive cells, and apoptotic morphology in cerebral tissues were associated with neurological deficit after SAH. JNK inhibition prevented c-Jun phosphorylation and suppressed AQP1, MMP-9, VEGF, and caspase-3 activation, with concomitant diminution of neuronal injury, blood-brain barrier preservation, reduced brain swelling, and improved neurological deficit in rats after SAH. This study demonstrates a multitude of beneficial effects of JNK inhibition, including protection of the neurovascular unit in early brain injury after SAH.
  • Yata K, Matchett G, Tsubokawa T, Tang J, Kanamara K, Zhang JH. "Granuloctye-colony stimulating factor inhibits apoptotic neuron loss after neonatal hypoxia-ischemia in rats." Brain Res 1145. (2007): 227-238. ( 5/2007 )
    Neonatal hypoxia-ischemia (HI) is an important clinical problem with few effective treatments. Granulocyte-colony stimulating factor (G-CSF) is an endogenous peptide hormone of the hematopoietic system that has been shown to be neuroprotective in focal ischemia in vivo and is currently in phase I/II clinical trials for ischemic stroke in humans. We tested G-CSF in a rat model of neonatal hypoxia-ischemia in postnatal day 7 unsexed rat pups. Three groups of animals were used: hypoxia-ischemia (HI, n=67), hypoxia-ischemia with G-CSF treatment (HI+G, n=65), and healthy control (C, n=53). G-CSF (50 microg/kg, subcutaneous) was administered 1 h after HI and given on four subsequent days (five total injections). Animals were euthanized 24 h, 1, 2, and 3 weeks after HI. Assessment included brain weight, histology, immunohistochemistry, and Western blotting. G-CSF treatment was associated with improved quantitative brain weight and qualitative Nissl histology after hypoxia-ischemia. TUNEL demonstrated reduced apoptosis in group HI+G. Western blot demonstrated decreased expression of Bax and cleaved caspase-3 in group HI+G. G-CSF treatment was also associated with increased expression of STAT3, Bcl-2, and Pim-1, all of which may have participated in the anti-apoptotic effect of the drug. We conclude that G-CSF ameliorates hypoxic-ischemic brain injury and that this may occur in part by an inhibition of apoptotic cell death.
  • Yatsushige H, Ostrowski R, Tsubokawa T, Colohan A, Zhang JH. "The role of c-Jun N-terminal Kinase in early brain injury after SAH." J Neurosci Res 85. (2007): 1436-1448. ( 5/2007 )
    The c-Jun N-terminal kinase (JNK) is induced by cerebral ischemia and injurious blood components acutely after subarachnoid hemorrhage (SAH). We hypothesized that inhibition of JNK will prevent damage to the neurovascular unit in the early brain injury period after SAH. Ninety-nine male SD rats (300-350 g) were randomly assigned to sham, SAH, and SAH treated with JNK inhibitor groups. SAH was induced by endovascular perforation. The JNK inhibitor SP600125 was administered intraperitoneally at 1 hr before and 6 hr after SAH. At 24 hr after SAH, we observed increased phosphorylation of JNK and c-Jun. Signs of neurovascular damage were observed in the hemorrhagic brains; these included the increases of aquaporin (AQP)-1 expression and brain water content as well as enhanced matrix metalloproteinase (MMP)-9 activity, vascular collagen IV loss, increased VEGF tissue level, and Evans blue extravasation. The appearances of cleaved caspase-3 expression, TUNEL-positive cells, and apoptotic morphology in cerebral tissues were associated with neurological deficit after SAH. JNK inhibition prevented c-Jun phosphorylation and suppressed AQP1, MMP-9, VEGF, and caspase-3 activation, with concomitant diminution of neuronal injury, blood-brain barrier preservation, reduced brain swelling, and improved neurological deficit in rats after SAH. This study demonstrates a multitude of beneficial effects of JNK inhibition, including protection of the neurovascular unit in early brain injury after SAH.
  • Jadhav C, Matchett G, Hsu FPK, Zhang JH. "Inhibition of Src Tyrosine Kinase improves outcomes in a new in vivo model of surgically induced brain injury." J Neurosurg 106. (2007): 680-688. ( 4/2007 )
    BACKGROUND: Neurosurgical procedures are carried out routinely in health institutions across the world. A key issue to be considered during neurosurgical interventions is that there is always an element of inevitable brain injury that results from the procedure itself because of the unique nature of the nervous system. Brain tissue at the periphery of the operative site is at risk of injury by various means, including incisions and direct trauma, electrocautery, hemorrhage, and retractor stretch. METHODS/RESULTS: In the present review, we will elaborate upon this surgically induced brain injury and also present a novel animal model to study it. In addition, we will summarize preliminary results obtained by pretreatment with PP1, an Src tyrosine kinase inhibitor reported to have neuroprotective properties in in vivo experimental studies. Any form of pretreatment to limit the damage to the susceptible functional brain tissue during neurosurgical procedures may have a significant impact on patient recovery. CONCLUSION: This brief review is intended to raise the question of 'neuroprotection against surgically induced brain injury' in the neurosurgical scientific community and stimulate discussions.
  • Calvert J, Zhang JH. "Oxyten treatment restores energy status following experimental neonatal hypoxia-ischemia." Pediatr Crit Care Med 2. (2007): 165-173. ( 3/2007 )
    OBJECTIVE: The purpose of this study was to determine whether oxygen treatment could attenuate the alterations in cerebral energy metabolism found in the brain following hypoxia-ischemia. DESIGN: Seven-day-old rat pups were subjected to unilateral carotid artery ligation followed by 2 hrs of hypoxia (8% oxygen at 37 degrees C). The concentrations of high-energy phosphate compounds and glycolytic intermediates and the activity of Na+/K+-adenosine triphosphatase were measured at 4-72 hrs of recovery. Brain weight was used to determine the severity of the brain injury at 2 wks after insult. SETTING: Experimental setting. SUBJECTS: Rat pups. INTERVENTIONS: Pups were treated with 100% oxygen 1 hr after the insult at 2.5 atmospheres absolute (hyperbaric oxygen) or at normobaric pressure for a duration of 2 hrs. MEASUREMENTS AND MAIN RESULTS: During the initial period of recovery from hypoxia-ischemia, values of adenosine triphosphate and phosphocreatine remained at levels below normal, whereas the levels of glucose and other glycolytic intermediates were elevated. Hyperbaric oxygen and normobaric oxygen both attenuated brain injury, restored the levels of adenosine triphosphate and phosphocreatine, decreased the levels of the glycolytic intermediates, and increased the utilization of energy. CONCLUSIONS: These results suggest that oxygen treatment during the initial period of recovery from a hypoxia-ischemic insult is able to attenuate energy deficits in the brain, which ultimately leads to a reduction in brain injury.
  • Tsubokawa T, Jadhav V, Solaroglu I, Shiokawa Y, Konisha Y, Zhang JH. "Lecithinized superoxide dismutase attenuates focal cerebral ischemic injury via anti-apoptotic mechanisms in rats." Stroke 3. (2007): 1057-1062. ( 3/2007 )
    BACKGROUND AND PURPOSE: Recent studies have shown the antiapoptotic neuroprotective effects of lecithinized superoxide dismutase (PC-SOD) in different forms of brain injury. We tested the effects of PC-SOD in focal cerebral ischemia in the rat middle cerebral artery occlusion model (MCAO). METHODS: Adult male Sprague-Dawley rats were treated with PC-SOD (0.3, 1.0, and 3.0 mg/kg) administered intravenously after 90 minutes of occlusion (beginning of reperfusion). Physiological parameters, neurological score, and infarct volume were assessed at 24 and 72 hours in 3 groups of animals: sham-operated (n=18), MCAO treated with vehicle (n=26), and MCAO treated with PC-SOD (n=37). Oxidative stress was evaluated by malondialdehyde assay, and the apoptotic mechanisms were studied by Western blotting. RESULTS: PC-SOD treatment significantly reduced infarct volume and improved neurological scores at different time points compared with the vehicle-treated group. PC-SOD treatment decreased malondialdehyde levels, cytochrome c, and cleaved caspase 3 expression and increased mitochondrial Bcl-2 expression. CONCLUSIONS: Inhibition of oxidative stress with PC-SOD treatment improves outcomes after focal cerebral ischemia. This neuroprotective effect is likely exerted by antiapoptotic mechanisms.
  • Matchett G, Calinisan J, Matchett G, Martin RD, Zhang JH. "The effect of granulocyte-colony stimulating factor in global cerfebral ischemia in rats." Brain Research 1136.9 (2007): 200-207. ( 3/2007 )
    Granulocyte-colony stimulating factor (G-CSF) is an endogenous peptide hormone of the hematopoietic system that has entered Phase I/II clinical trials for treatment of ischemic stroke. Severe intraoperative hypotension can lead to global cerebral ischemia and apoptotic neuron loss within the hippocampus. We tested G-CSF in a rat model of global cerebral ischemia. Global cerebral ischemia was induced in male Sprague-Dawley rats (280-330 g) with the 2-vessel occlusion model (hemorrhagic hypotension to a mean arterial pressure of 30-35 mm Hg and bilateral common carotid artery occlusion for 8 min). Three groups of animals were used: global ischemia without treatment (GI, n=49), global ischemia with G-CSF treatment (GI+G-CSF, n=42), and sham surgery (Sham, n=26). Rats in the treatment group received G-CSF (50 mug/kg, subcutaneously) 12 h before surgery, on the day of surgery, and on postoperative Day 1 and were euthanized on Days 2, 3, and 14. Mild hyperglycemia was observed in all groups. T-maze testing for spontaneous alternation demonstrated initial improvement in the G-CSF treatment group but no long-term benefit. Measurement of daily body weight demonstrated an initial trend toward improvement in the G-CSF group. Quantitative Nissl histology of the hippocampus demonstrated equivalent outcomes on Days 3 and 14, which was supported by quantitative TUNEL stain. Immunohistochemistry and Western blot demonstrated an initial increase in phosphorylated-AKT in the GI+G-CSF group on Day 2. We conclude that G-CSF treatment is associated with transient early improvement in neurobehavioral outcomes after global ischemia complicated by mild hyperglycemia, but no long-term protection.
  • Huang Z, Kang Z, Gu G, Peng G, Liu Y, Tao H, Xu W, Zhang JH, Sun X. "Therapeutic effects of hyperbaric oxygen in a rat model of endothelin-1 induced focal cerebral ischemia." Brain Res 1153. (2007): 204-213. ( 3/2007 )
  • Yata K Matchett G, Tsubokawa T, Tang J, Kanamaru K, Zhang JH. "Granulocyte-colony stimulating factor inhibits apoptotic neuron loss after neonatal hypoxia-ischemia in rats." Brain Research 1153. (2007): 204-213. ( 3/2007 )
  • Yata K, Matchett G, Tsubokawa T, Tang J, Kanamaru K, Zhang JH. "Granulocyte-colony stimulating factors inhibits apoptotic neuronal loss after neonatal hypoxia-ischemia in rats." Brain Research 1145. (2007): 227-238. ( 3/2007 )
    Neonatal hypoxia-ischemia (HI) is an important clinical problem with few effective treatments. Granulocyte-colony stimulating factor (G-CSF) is an endogenous peptide hormone of the hematopoietic system that has been shown to be neuroprotective in focal ischemia in vivo and is currently in phase I/II clinical trials for ischemic stroke in humans. We tested G-CSF in a rat model of neonatal hypoxia-ischemia in postnatal day 7 unsexed rat pups. Three groups of animals were used: hypoxia-ischemia (HI, n=67), hypoxia-ischemia with G-CSF treatment (HI+G, n=65), and healthy control (C, n=53). G-CSF (50 microg/kg, subcutaneous) was administered 1 h after HI and given on four subsequent days (five total injections). Animals were euthanized 24 h, 1, 2, and 3 weeks after HI. Assessment included brain weight, histology, immunohistochemistry, and Western blotting. G-CSF treatment was associated with improved quantitative brain weight and qualitative Nissl histology after hypoxia-ischemia. TUNEL demonstrated reduced apoptosis in group HI+G. Western blot demonstrated decreased expression of Bax and cleaved caspase-3 in group HI+G. G-CSF treatment was also associated with increased expression of STAT3, Bcl-2, and Pim-1, all of which may have participated in the anti-apoptotic effect of the drug. We conclude that G-CSF ameliorates hypoxic-ischemic brain injury and that this may occur in part by an inhibition of apoptotic cell death.
  • Lo W, Brava T, Jadhav V, Titova E, Zhang JH, Tang J. "NADPH Oxidase Inhibition Improves Neurological Outcomes in Surgically-induced brain injury." Neurosci Lett 414.3 (2007): 228-232. ( 3/2007 )
    Neurosurgical procedures can result in brain injury by various means including direct trauma, hemorrhage, retractor stretch, and electrocautery. This surgically-induced brain injury (SBI) can cause post-operative complications such as brain edema. By creating a mouse model of SBI, we tested whether NADPH oxidase, an important reactive oxygen species producing enzyme, is involved in SBI using transgenic mice lacking gp91phox subunit of NADPH oxidase (gp91phox KO) and apocynin, a specific inhibitor of NADPH oxidase. Neurological function and brain edema were evaluated at 24 h post-SBI in gp91phox KO and wild-type littermates grouped into SBI and sham-surgery groups. Alternatively, mice were grouped into vehicle- and apocynin-treated (5 mg/kg, i.p. 30 min before SBI) groups. Oxidative stress indicated by lipid peroxidation (LPO) was measured at 3 and 24 h post-SBI. The gp91phox KO mice, but not the apocynin-treated mice showed significantly improved neurological scores. Brain edema was observed in both gp91phox KO and wild-type groups after SBI; however, there was no significant difference between these two groups. Brain edema was also not affected by apocynin-pretreatment. LPO levels were significantly higher in SBI group in both gp91phox KO and wild-type groups as compared to sham group. A trend, although without statistical significance, was noted towards attenuation of LPO in the gp91phox KO animals as compared to wild-type group. LPO levels were significantly attenuated at 3 h post-SBI by apocynin-pretreatment but not at 24 h post-SBI. These results suggest that chronic and acute inhibition of NADPH oxidase activity does not reduce brain edema after SBI. Long-term inhibition of NADPH oxidase, however improves neurological functions after SBI.
  • Shimamura N, Matchett G, Tsubokawa T, Ohkuma H, Zhang JH. "Comparison of silicon-coated nylon sutre to plain nylon suture in the rat middle cerebral artery occlusion model." J Neurosci Methods 156.9 (2006): 161-165. ( 9/2006 )
  • Tsubokawa T, Solaroglu I, Yatsushige H, Cahill J, Yata K, Zhang JH. "Cathepsin and calpain inhibitor E64d attenuates matrix metaloprotease-9 activity after focal cerebral ischemia." Stroke . (2006): 1888-1894. ( 7/2006 )
    BACKGROUND AND PURPOSE: Matrix metalloproteinases (MMPs) and cysteine proteases (calpain and cathepsin B) play an important role in cell death and are upregulated after focal cerebral ischemia. Because there is a significant interaction between MMP-9 with calpain and cathepsin B, we investigated the role of E64d (a calpain and cathepsin B inhibitor) on MMP-9 activation in the rat focal ischemia model. METHODS: Male Sprague-Dawley rats were subjected to 2 hours of middle cerebral artery occlusion by using the suture insertion method followed by 22 hours of reperfusion. In the treatment group, a single dose of E64d (5 mg/kg IP) was administrated 30 minutes before the induction of focal ischemia, whereas the nontreatment group received dimethyl sulfoxide only. The neurological deficits, infarct volumes, Evans blue extravasation, brain edema, and MMP-9 activation in the brain were determined. RESULTS: Pretreatment with E64d produced a significant reduction in the cerebral infarction volume (353.1+/-19.8 versus 210.3+/-23.7 mm3) and the neurological deficits. Immunofluorescence studies showed MMP-9, calpain, and cathepsin B activation colocalized to both neurons and the neurovascular endothelial cells after ischemia, which was reduced by E64d. CONCLUSIONS: These results suggest that E64d treatment provides a neuroprotective effect to rats after transient focal cerebral ischemia by inhibiting the upregulation of MMP-9.
  • Shimamura N, Yatsushige H, Matchett, G, Calvert J, Ohkuma H, Zhang JH. "Inhibition of integrin av33 ameliorates focal cerebral ischemic damage in the rat middle cerebral artery occlusion model." Stroke 37.7 (2006): 1902-1909. ( 7/2006 )
    BACKGROUND AND PURPOSE: Recent studies have shown that selective inhibition of specific subsets of intercellular adhesion molecules protects the brain during ischemia. We studied selective inhibition of integrin alphavbeta3 with cyclo [Arg-Gly-Asp-D-Phe-Val] (cRGDfV) in the rat middle cerebral artery occlusion model (MCAO). METHODS: Rats were treated before and after MCAO with cRGDfV. Physiological parameters, expression of integrin alphavbeta3, infarction volume, brain water content, Evans Blue exudation, IgG exudation, histology, immunohistochemistry, and western blotting were studied in 4 groups of animals: sham operation (n=13), untreated (n=18), nonfunctioning peptide treatment (n=19), and cRGDfV treatment (n=27). RESULTS: Treatment with cRGDfV reduced infarction, reduced brain edema, reduced exudation of Evans blue and IgG, and prevented fibrinogen deposition. Western blotting showed reduction of phosphorylated Flk-1 (a vascular endothelial growth factor [VEGF] receptor), reduction of phosphorylated FAK (an intracellular kinase phosphorylated in the presence of VEGF), reduction of VEGF, and reduction of fibrinogen in the cRGDfV treatment group. CONCLUSIONS: The selective integrin alphavbeta3 inhibitor cRGDfV improves outcomes in the MCAO model by preserving the blood-brain barrier, which mechanistically may occur in a VEGF- and VEGF-receptor-dependent manner.
  • Armin S, Colohan A, Zhang JH. "Traumatic subarachnoid hemorrhage: our current understanding and its evolution over the past half century." Neurol Res 28.4 (2006): 445-452. ( 6/2006 )
    Traumatic brain injury (TBI) is a common cause of morbidity and mortality in the US, especially among the young. Primary injury in TBI is preventable, whereas secondary injury is treatable. As a result, considerable research efforts have been focused on elucidating the pathophysiology of secondary injury and determining various prognosticators in the hopes of improving final outcome by minimizing secondary injury. One such variable, traumatic subarachnoid hemorrhage (tSAH), has been the focus of many discussions over the past half century as numerous clinical studies have shown tSAH to be associated with adverse outcome. Whether the relationship of tSAH with poorer outcome in TBI is merely an epiphenomenon or a result of direct cause and effect is unclear. Some investigators believe that tSAH is merely a marker of severer TBI, while others argue that it directly causes deleterious effects such as vasospasm and ischemia. At the present time, no proven treatment regimen aimed specifically at decreasing the detrimental effects of tSAH exists, although calcium channel blockers traditionally thought to target vasospasm have shown some promises. Given that tSAH may primarily be an early indicator of associated and evolving brain injury, vigilant diagnostic surveillance including serial head CT and prevention of secondary brain damage owing to hypotension, hypoxia and intracranial hypertension may be more cost-effective than attempting to treat potential adverse sequelae associated with tSAH.
  • Ostrowski R, Colohan A, Zhang JH. "Molecular mechanisms of early brain injury after subarachnoid hemorrhage (review)." Neurol Res . (2006): 399-414. ( 6/2006 )
    OBJECTIVES: Increasing body of experimental and clinical data indicates that early brain injury after initial bleeding largely contributes to unfavorable outcome after subarachnoid hemorrhage (SAH). This review presents molecular mechanisms underlying brain injury at its early stages after SAH. METHODS: PubMed was searched using term 'subarachnoid hemorrhage' and key words referring to molecular and cellular pathomechanisms of SAH-induced early brain injury. RESULTS: The authors reviewed intracranial phenomena and molecular agents that contribute to the early development of pathological sequelae of SAH in cerebral and vascular tissues, including cerebral ischemia and its interactions with injurious blood components, blood-brain barrier disruption, brain edema and apoptosis. DISCUSSION: It is believed that detailed knowledge of molecular signaling pathways after SAH will serve to improve therapeutic interventions. The most promising approach is the protection of neurovascular unit including anti-apoptosis therapy.
  • Solaroglu I, Cahill J, Jadhav V, Zhang JH. "Response to letter by Schabitz, et al (Epub)." Stroke . (2006): 000-000. ( 5/2006 )
  • Ostrowski R, Tang J, Zhang JH. "Hyperbaric Oxygen suppresses NADPH oxidase in a rat subarachnoid hemorrhage model." Stroke . (2006): 1314-1318. ( 5/2006 )
    BACKGROUND AND PURPOSE: One of the major contributors to brain injury after subarachnoid hemorrhage (SAH) is oxidative stress, and 1 of the major enzymatic sources of superoxide anion production in the brain is NADPH oxidase. Therefore, we studied whether hyperbaric oxygen (HBO) suppresses neuronal NADPH oxidase in a rat model of SAH. METHODS: Eighty-three Sprague-Dawley male rats were assigned to sham, SAH, and SAH treated with HBO groups. SAH was induced by endovascular perforation. HBO (2.8 atmospheres absolutes for 2 hours) was started at 1 hour after perforation. Rats were euthanized at 6 or 24 hours, and brains were collected for histology, biochemistry, and molecular biology studies including NADPH oxidase activity, gp91phox mRNA expression, and lipid peroxidation assays. Mortality and neurological scores were evaluated. RESULTS: We observed an increased neuronal immunoreactivity of gp91phox at 24 hours after SAH. The upregulation of gp91phox mRNA was associated with increased oxidative stress. HBO decreased NADPH oxidase expression, activity, and the level of oxidative stress at 24 hours after SAH. HBO reduced neuronal injury and improved functional performance throughout the observation period. CONCLUSIONS: HBO suppresses NADPH oxidase and oxidative stress in cerebral tissues at 24 hours after SAH.
  • Li Y, Zhou C, Calvert W, Colohan A, Zhang JH. "Multiple feffects of HBO on HIF1 a Expression and apoptotic genes in global ischemia rat model." Experimental Neurology 191. (2006): 198-210. ( 5/2006 )
  • Solaroglu I, Cahill J, Jadhav V, Zhang JH. "A novel neuroprotectant granulocyte-colony stimulating factor (review)." Stroke . (2006): 1123-1128. ( 5/2006 )
    BACKGROUND AND PURPOSE: Granulocyte-colony stimulating factor (G-CSF) is a growth factor that orchestrates the proliferation, differentiation, and survival of hematopoietic progenitor cells. It has been used for many years in clinical practice to accelerate the recovery of patients from neutropenia after cytotoxic therapy. However, there is a growing body of evidence from experimental studies suggesting that G-CSF also has important nonhematopoietic functions in the central nervous system. SUMMARY OF REVIEW: The presence of the G-CSF/G-CSF-receptor system in the brain and its role in neuroprotection and neural tissue repair has been investigated in many recent studies. The neuroprotective actions of G-CSF have mainly been attributed to its anti-inflammatory and antiapoptotic effects. Furthermore, it induces neurogenesis and angiogenesis and improves functional recovery. In this review, we summarize the role of G-CSF and the corresponding signal transduction pathways regulated by G-CSF in neuroprotection. CONCLUSIONS: Much additional work is needed to better understand the precise mechanisms of G-CSF-induced neuroprotection. However, there is emerging data suggesting that G-CSF is a potential new agent for neuroprotection.
  • Zhang JH. "Introduction: Cerebral Vascular Diseases." Pathophysiology 12.1 (2005): 3-4. ( 12/2005 )
  • Yamaguchi M, Calvert J, Kusaka G, Zhang JH. "One-stage anterior approach for four-vessel occlusion in rat.." Stroke 36.10 (2005): 2212-2214. ( 10/2005 )
    BACKGROUND AND PURPOSE: We report a modified 4-vessel occlusion (4VO) rat model. METHOD: We used a 1-stage anterior approach for making bilateral hemispheric ischemia. RESULTS: Modified 4VO method decreased cerebral blood flow to 12% to 14% of baseline levels. CONCLUSIONS: This modified 4VO method is a minimally invasive, quick, reliable procedure for producing ischemic changes.
  • Patwardhan RV, Besio W, Calvert JW, Kusaka G, Kusaka I, Zhang J, Nanda A.. "Electroconvulsive therapy for seizure control: preliminary data in a new seizure generation and control model.." Front Biosci 1.10 (2005): 1013-3019. ( 9/2005 )
    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.
  • Patwardhan RV, Calvert JW, Besio W, Kusaka G, Kusaka I, Zhang J, Nanda A.. "Technical note: preliminary results in development of a novel intracisternal penicillin seizure model in the rat.." Front Biosci 3009.3012 (2005): 1-10. ( 9/2005 )
    In order to develop an intracisternal penicillin rat model of epilepsy, eleven anesthetized male Wistar rats were studied. 5 underwent intracisternal injection of penicillin (doses 150,000-300,000 units) in the prone position, and another 5 underwent intraperitoneal penicillin injection; one died following intracisternal injection, prior to further study. Time between penicillin injection and seizure induction (determined by electroencephalography) was recorded. Each animal had a tracheostomy, and was mechanically ventilated and carefully monitored for adverse effects. Seizures were noted in an average of 13:42 minutes following penicillin injection (range 4:30-23:20) for the intracisternally (IC) injected group. Both episodic and continuous seizure activity was seen, and a dose-dependent effect was seen (quicker-onset, more continuous seizures with higher doses, in the IC group). Onset was significantly faster in the IC than for the intraperitoneally injected group (all >1 hour for the latter group in our study). 96 total separate seizure episodes were seen, ranging from 3 to 540 seconds. Epileptic activity could be seen in all IC-injected rats lasting over 1 hour into the study. The intracisternal penicillin injection rat model appears to provide a quick-onset, reliable method of inducing seizure activity in the rat model while leaving the cranial vault intact.
  • Tang J, Liu J, Zhou C, Ostanin D, Grisham MB, Neil Granger D, Zhang JH.. "Role of NADPH oxidase in the brain injury of intracerebral hemorrhage.." J Neurochem. 94.5 (2005): 1342-1350. ( 9/2005 )
    The major risk factors for intracerebral hemorrhage (ICH) are hypertension and aging. A fundamental mechanism for hypertension- and aging-induced vascular injury is oxidative stress. We hypothesize that oxidative stress has a crucial role in ICH. To test our hypothesis, we used bacterial collagenase to produce ICH in wild-type C57BL/6 and gp91phox knockout (gp91phox KO) mice (deficient in gp91phox subunit of the superoxide-producing enzyme NADPH oxidase). All animals were studied at 20-35 weeks of age, resembling an older patient population. We found that collagenase produced less bleeding in gp91phox KO mice than wild-type mice. Total oxidative product was lower in gp91phox KO mice than in wild-type mice, both under basal conditions and after ICH. Consistent with the ICH volume, brain edema formation, neurological deficit and a high mortality rate was noted in wild-type but not in gp91phox KO mice. This ICH-induced brain injury in wild-type mice is associated with enhanced expression of the gp91phox subunit of NADPH oxidase. In conclusion, the oxidative stress resulting from activation of NADPH oxidase contributes to ICH induced by collagenase and promotes brain injury.
  • Dai Y, Tang J, Zhang JH.. "Role of Cl- in cerebral vascular tone and expression of Na+-K+-2Cl- co-transporter after neonatal hypoxia-ischemia.." Can J Physiol Pharmacol. 83.8-9 (2005): 767-773. ( 8/2005 )
    Chloride (Cl-) efflux induces depolarization and contraction of vascular smooth muscle cells. In the basilar arteries from the New Zealand white rabbits, the role of Cl- flux in serotonin-induced contraction was demonstrated by (i) inhibition of Na+-K+-2Cl- co-transporter (NKCC1) to decreased Cl- influx with bumetanide; (ii) a disabled Cl-/HCO3- exchanger with bicarbonate free HEPES solution; (iii) blockade of Cl- channels using 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) and indanyloxyacetic acid 94, R-(+)-methylindazone (R-(+)-IAA-94); and (iv) substitution of extracellular Cl- with methanesulfonate acid (113 mmol/L; Cl-, 10 mmol/L). In addition, the expression of NKCC1 in brain tissues after neonatal hypoxia-ischemia was examined at mRNA and protein levels using RT-PCR and Western blotting techniques. NKCC1 mRNA and protein expressions were increased at 24 and 48 h and returned to normal levels at 72 h after hypoxia insult when compared with the control littermates. In conclusion, Cl- efflux regulates cerebral circulation and the up-regulation of NKCC1 after neonatal hypoxia-ischemia may contribute to brain injury.
  • Tang J, Fitzgerald SM, Boughtman BN, Cole SW, Brands MW, Zhang JH.. "Decreased RhoA expression in myocardium of diabetic rats.." Can J Physiol Pharmacol. 83.8-9 (2005): 775-783. ( 8/2005 )
    Diabetic cardiomyopathy is 1 of the major causes of death in diabetic patients, but the pathogenesis is unclear. There is evidence that RhoA, a small GTPase, might be involved in cardiac function. This study, therefore, analyzed RhoA expression and activation in hearts of diabetic rats. Male Sprague-Dawley rats were divided into control and diabetic groups of 18 each. Diabetes was induced by intravenous injection of streptozotocin (55 mg/kg). Rats were studied 3 weeks after induction of diabetes. Heart rate, which was measured 24 h/day, decreased by 93 +/- 7 beats/min in diabetic rats. There was a 62% decrease (p < 0.01) in RhoA mRNA expression in heart tissues (left ventricle) of diabetic rats (38.5 +/- 6.7 x 106 molecules/microg total RNA) compared with controls (101 +/- 10.3 x 106 molecules/microg total RNA). Western blot showed a 33% decrease in total RhoA protein expression in heart tissues of diabetic rats compared with controls (p < 0.05). A reduced RhoA translocation in heart tissues of diabetic rats was determined by a 64% decrease in membrane-bound RhoA (p < 0.01 vs. control group), indicating that the activation of RhoA is markedly reduced in diabetic myocardium. Our data suggest that down-regulated RhoA may be involved in cardiomyopathy in diabetic rats.
  • Zhang JH, Lo T, Mychaskiw G, Colohan A.. "Mechanisms of hyperbaric oxygen and neuroprotection in stroke.." Pathophysiology. 2005 Jul;12(1):63-77. 12.1 (2005): 63-11. ( 7/2005 )
    Cerebral vascular diseases, such as neonatal encephalopathy and focal or global cerebral ischemia, all result in reduction of blood flow to the affected regions, and cause hypoxia-ischemia, disorder of energy metabolism, activation of pathogenic cascades, and eventual cell death. Due to a narrow therapeutic window for neuroprotection, few effective therapies are available, and prognosis for patients with these neurological injuries remains poor. Hyperbaric oxygen (HBO) has been used as a primary or adjunctive therapy over the last 50 years with controversial results, both in experimental and clinical studies. In addition, the mechanisms of HBO on neuroprotection remain elusive. Early applications of HBO within a therapeutic window of 3-6h or delayed but repeated administration of HBO can either salvage injured neuronal tissues or promote neurobehavioral functional recovery. This review explores the discrepancies between experimental and clinical observations of HBO, focusing on its therapeutic window in brain injuries, and discusses the potential mechanisms of HBO neuroprotection.
  • Sun Y, Calvert J, Zhang JH. "EPO decreases inflammatory cytokines induced by hypoxia-icshemia in neonatal rats." Stroke 36.1 (2005): 1672-1678. ( 7/2005 )
  • Yatsushige H, Yamaguchi M, Zhou C, Calvert JW, Zhang JH.. "Role of c-Jun N-terminal kinase in cerebral vasospasm after experimental subarachnoid hemorrhage.." Stroke 36.7 (2005): 1538-1543. ( 7/2005 )
    BACKGROUND AND PURPOSE: Inflammation could play a role in cerebral vasospasm after subarachnoid hemorrhage (SAH). SP600125 a c-Jun N-terminal kinase (JNK) inhibitor reduces inflammation. The present study examined if SP600125 could reduce cerebral vasospasm. METHODS: Twenty-seven dogs were assigned to 5 groups: control, SAH, SAH plus dimethyl sulfoxide (DMSO), SAH plus SP600125 (10 micromol/L), and SAH plus SP600125 (30 micromol/L). SAH was induced by the injection of autologous blood into the cisterna magna on day 0 and day 2. Angiograms were evaluated on day 0 and day 7. The behavior of the dogs was evaluated daily. The activation of the JNK pathway, the infiltration of leukocytes, and the production of cytokines were also evaluated. RESULTS: Severe vasospasm was observed in the basilar artery of SAH and DMSO dogs. The JNK signaling pathway was activated in the basilar artery after SAH and SP600125 reduced angiographic and morphological vasospasm and improved behavior scores with a concomitant reduction of infiltrated leukocytes and IL-6 production. CONCLUSIONS: These results demonstrate that SP600125 attenuated cerebral vasospasm through a suppressed inflammatory response, which may provide a novel therapeutic target for cerebral vasospasm.
  • Zhang JH, Lo T, Mychaskiw G, Colohan A.. "Mechanisms of hyperbaric oxygen and neuroprotection in stroke.." Pathophysiology 12.1 (2005): 63-44. ( 7/2005 )
    Department of Neurosurgery, Loma Linda University, Loma Linda, CA, USA; Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, USA. Cerebral vascular diseases, such as neonatal encephalopathy and focal or global cerebral ischemia, all result in reduction of blood flow to the affected regions, and cause hypoxia-ischemia, disorder of energy metabolism, activation of pathogenic cascades, and eventual cell death. Due to a narrow therapeutic window for neuroprotection, few effective therapies are available, and prognosis for patients with these neurological injuries remains poor. Hyperbaric oxygen (HBO) has been used as a primary or adjunctive therapy over the last 50 years with controversial results, both in experimental and clinical studies. In addition, the mechanisms of HBO on neuroprotection remain elusive. Early applications of HBO within a therapeutic window of 3-6h or delayed but repeated administration of HBO can either salvage injured neuronal tissues or promote neurobehavioral functional recovery. This review explores the discrepancies between experimental and clinical observations of HBO, focusing on its therapeutic window in brain injuries, and discusses the potential mechanisms of HBO neuroprotection.
  • Yatsushige H, Yamaguchi M, Zhou C, Calvert JW, Zhang JH.. "Role of c-Jun N-terminal kinase in cerebral vasospasm after experimental subarachnoid hemorrhage.." Stroke 36.7 (2005): 1538-1543. ( 7/2005 )
    BACKGROUND AND PURPOSE: Inflammation could play a role in cerebral vasospasm after subarachnoid hemorrhage (SAH). SP600125 a c-Jun N-terminal kinase (JNK) inhibitor reduces inflammation. The present study examined if SP600125 could reduce cerebral vasospasm. METHODS: Twenty-seven dogs were assigned to 5 groups: control, SAH, SAH plus dimethyl sulfoxide (DMSO), SAH plus SP600125 (10 micromol/L), and SAH plus SP600125 (30 micromol/L). SAH was induced by the injection of autologous blood into the cisterna magna on day 0 and day 2. Angiograms were evaluated on day 0 and day 7. The behavior of the dogs was evaluated daily. The activation of the JNK pathway, the infiltration of leukocytes, and the production of cytokines were also evaluated. RESULTS: Severe vasospasm was observed in the basilar artery of SAH and DMSO dogs. The JNK signaling pathway was activated in the basilar artery after SAH and SP600125 reduced angiographic and morphological vasospasm and improved behavior scores with a concomitant reduction of infiltrated leukocytes and IL-6 production. CONCLUSIONS: These results demonstrate that SP600125 attenuated cerebral vasospasm through a suppressed inflammatory response, which may provide a novel therapeutic target for cerebral vasospasm.
  • Cahill J, Calvert I, Solaroglu H, Zhang JH. "Vasospasm and p53 induced apoptosis in an experimental model of subarachnoid hemorrhage." Stroke . (1969): 1888-1894. (*)
  • Sun Y, Calvert J, Zhang JH. "EPO decreases inflammatory cytokines induced by hypoxia-ischemia in neonatal rats." Stroke 36. (1969): 1672-1678. (*)
  Books and Chapters
  • Editor, Special Journal Issue:  Molecular Neurosurgery. Neurol Research, December 2007 ( 12/2007 )
  • Ostrowski R, Colohan A, Zhang JH. Acute Ischemic Injury and repair in the nervous system (in) Handbook of Neurochemistry and molecular neurobiology. New York NY: Humana Press, 2007. 235 - 253 ( 1/2007 )
  • Zhang (Ed). Hyperbaric Oxygen of Neurological Diseases. Flagstaff, AZ: Best Publishing, 2007. ( 1/2007 )
  • Kiris T, Zhang JH (Eds). Cerebral Vasospasm IX. New York, NY: Springer Wein, 2007. ( 1/2007 )
  • Zhang JH (Ed). Advances of Clinical Neurological Research. Kerala, India: Signpost, 2007. ( 1/2007 )
  • Chen J, Xiaoming X, Zao C, Zhang JH (Eds). Animal Models of Acute Neurological Injuries. New York, NY: Humana Press, 2007. ( 1/2007 )
  • Ostrowski R, Zhang JH. Mechanisms of Hyperbaric Oxyten Induced Neuroprotection (Ed Zhang JH). Flagstaff AZ: Best Publishing, 2007. ( 1/2007 )
  • Ren P, Sun XJ, Zhang JH. Hyperbaric oxygen for carbon monoxide poisoning . (Ed: Zhang JH). Flagstaff, AZ: Best Publishing, 2007. ( 1/2007 )
  • Cahill J, Zhang JH. Early Brain Injury and the role of apoptosis after subarachnoid hemorrhage. Kelara India: Research Signpost, 2007. ( 1/2007 )
  • Matchett G, Higushi C, Allard M, Zhang JH (Ed: Zhang JH). Volatile anesthetics and cerebral ischemia: Neurportective mechanisms, clinical implicartions. Kerala India: Research Signpost, 2007. ( 1/2007 )
  • Ostrowski R, Colohan A, Zhang JH (Ed Chan P). Molecular signaling pathways in early brain injury after SAH. New York NY: Humana Press, 2007. ( 1/2007 )
  • Himamura H, Gules I, Chen B, Meguro T, Parent A, Zhang JH. Cytokines Produce Apoptosis in Cultured Cerebral Endothelial. Cerebral Vasospasm: Thieme, 2004. 97 - 204 ( 7/2004 )
  • Kiris K, Zhang JH (Eds). Cerebral Vasospasm IX. New York, NY: Springer Wien, . (*)