PubMed Health⌕ Search

Biomedical subjects

H S Sharma

Publications and source records attributed to H S Sharma.

At least 19 recordsLinked to original sources
PubMed2006

Zinc protoporphyrin IX attenuates closed head injury-induced edema formation, blood-brain barrier disruption, and serotonin levels in the rat.

The role of heme oxygenase (HO) in closed head injury (CHI) was examined using a potent HO and guanylyl cyclase inhibitor, zinc protoporphyrin (Zn-PP) in the rat. Blood-brain barrier (BBB) permeability to Evans blue and radioiodine, edema formation, and plasma and brain levels of serotonin were measured in control, CHI, and Zn-PP-treated CHI rats. CHI was produced by an impact of 0.224 N on the right parietal bone by dropping 114.6 g weight from a height of 20 cm in anesthetized rats. This concussive injury resulted in edema formation and brain swelling 5 hours after insult that was most pronounced in the contralateral hemisphere. The whole brain was edematous and remained in a semi-fluid state. Microvascular permeability disturbances to protein tracers were prominent in both cerebral hemispheres and the underlying cerebral structures. Plasma and brain serotonin showed pronounced increases and correlated with edema formation. Pretreatment with Zn-PP (10 mg/ kg, i.p) 30 minutes before or after CHI attenuated edema formation, brain swelling, plasma and brain serotonin levels, and microvascular permeability at 5 hours. Brain edema, BBB permeability, and serotonin levels were not attenuated when the compound was administered 60 minutes post-CHI suggesting that HO is involved in cellular and molecular mechanisms of edema formation and BBB breakdown early after CHI.

Animals↗
PubMed2006

Topical application of dynorphin A (1-17) antibodies attenuates neuronal nitric oxide synthase up-regulation, edema formation, and cell injury following focal trauma to the rat spinal cord.

Previous investigations from our laboratory show that up-regulation of neuronal nitric oxide synthase (NOS) following spinal cord injury (SCI) is injurious to the cord. Antiserum to dynorphin A (1-17) induces marked neuroprotection in our model of SCI, indicating an interaction between dynorphin and NOS regulation. The present investigation was undertaken to find out whether topical application of dynorphin A (1-17) antiserum has some influence on neuronal NOS up-regulation in the traumatized spinal cord. SCI was produced in anesthetized animals by making a unilateral incision into the right dorsal horn of the T10-11 segments. The antiserum to dynorphin A (1-17) was applied (1 : 20, 20 microL in 10 seconds) 5 minutes after trauma over the injured spinal cord and the rats were allowed to survive 5 hours after SCI. Topical application of dynorphin A (1-17) antiserum significantly attenuated neuronal NOS up-regulation in the adjacent T9 and T12 segments. In the antiserum-treated group, spinal cord edema and cell injury were also less marked. These observations provide new evidence that the opioid active peptide dynorphin A may be involved in the mechanisms underlying NOS regulation in the spinal cord after injury, and confirms our hypothesis that up-regulation of neuronal NOS is injurious to the cord.

Animals↗
PubMed2006

Histamine receptors influence blood-spinal cord barrier permeability, edema formation, and spinal cord blood flow following trauma to the rat spinal cord.

The role of histamine in edema formation, blood-spinal cord barrier (BSCB) permeability, and spinal cord blood flow (SCBF) following spinal cord injury (SCI) was examined using modulation of histamine H1, H2, and H3 receptors in the rat. Focal trauma to the spinal cord at the T10-11 level significantly increased spinal cord edema formation, BSCB permeability to protein tracers and SCBF reduction in the T9 and T12 segments. Pretreatment with histamine H1 receptor antagonist mepyramine (1 mg, 5 mg, and 10 mg/kg, i.p.) did not attenuate spinal pathophysiology following SCI. Blockade of histamine H2 receptors with cimetidine or ranitidine (1 mg, 5 mg, or 10 mg/kg 30 minutes before injury) significantly reduced early pathophysiological events in a dose dependent manner. The effects of ranitidine were far superior to cimetidine in identical doses. Pretreatment with a histamine H3 receptor agonist alpha-methylhistamine (1 mg and 2 mg/kg/i.p.), that inhibits histamine synthesis and release in the CNS, thwarted edema formation, BSCB breakdown, and SCBF disturbances after SCI. The lowest dose of histamine H3 agonist was most effective. Blockade of histamine H3 receptors with thioperamide (1 mg, 5 mg/kg, i.p.) exacerbated spinal cord pathology. These observations suggest that stimulation of histamine H3 receptors and blockade of histamine H2 receptors is neuroprotective in SCI.

Animals↗
PubMed2006

Post-injury treatment with a new antioxidant compound H-290/51 attenuates spinal cord trauma-induced c-fos expression, motor dysfunction, edema formation, and cell injury in the rat.

The neuroprotective efficacy of post-injury treatment with the antioxidant compound H-290/51 (10, 30, and 60 minutes after trauma) on immediate early gene expression (c-fos), blood-spinal cord barrier (BSCB) permeability, edema formation, and motor dysfunction was examined in a rat model of spinal cord injury (SCI). SCI was produced by a longitudinal incision into the right dorsal horn of the T10-11 segment under Equithesin anesthesia. Focal SCI in control rats resulted in profound up-regulation of c-fos expression, BSCB dysfunction, edema formation, and cell damage in the adjacent T9 and T12 segments at 5 hours. Pronounced motor dysfunction was present at this time as assessed using the Tarlov scale and the inclined plane test. Treatment with H-290/51 (50 mg/kg, p.o.) 10 and 30 minutes after SCI (but not after 60 minutes) markedly attenuated c-fos expression and motor dysfunction. In these groups, BSCB permeability, edema formation, and cell injuries were mildly but significantly reduced. These observations suggest that (i) antioxidants are capable of attenuating cellular and molecular events following trauma, and (ii) have the capacity to induce neuroprotection and improve motor function if administered during the early phase of SCI, a novel finding.

Animals↗
PubMed2006

Post-traumatic application of brain-derived neurotrophic factor and glia-derived neurotrophic factor on the rat spinal cord enhances neuroprotection and improves motor function.

We examined the potential efficacy of brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) applied over traumatized spinal cord, alone or in combination, for attenuating motor dysfunction, blood-spinal cord barrier (BSCB) breakdown, edema formation, and cell injury in a rat model. Under Equithesin anesthesia, spinal cord injury (SCI) was performed by making a unilateral incision into the right dorsal horn of the T10-11 segment. The rats were allowed to survive 5 hours after trauma. The BDNF or GDNF was applied (0.1 to 1 microg/10 microl in phosphate buffer saline) 30, 60, or 90 minutes after SCI. Topical application of BDNF or GDNF 30 minutes after SCI in high concentration (0.5 microg and 1 microg) significantly improved motor function and reduced BSCB breakdown, edema formation, and cell injury at 5 hours. These beneficial effects of neurotrophins were markedly absent when administered separately either 60 or 90 minutes after injury. However, combined application of BDNF and GDNF at 60 or 90 minutes after SCI resulted in a significant reduction in motor dysfunction and spinal cord pathology. These novel observations suggest that neurotrophins in combination have potential therapeutic value for the treatment of SCI in clinical situations.

Animals↗
PubMed2006

Chronic spinal nerve ligation induces microvascular permeability disturbances, astrocytic reaction, and structural changes in the rat spinal cord.

The possibility that a chronic nerve ligation impairs the spinal cord cellular microenvironment was examined using leakage of endogenous albumin, reaction of astrocytes, and structural changes in a rat model. Rats subjected to 8 weeks of unilateral L4/L5 nerve ligation (a model of neuropathic pain) showed leakage of albumin, up-regulation of glial fibrillary acidic protein (GFAP) immunoreaction, and abnormal cell reaction. Distortion and loss of nerve cells as well as general sponginess of the gray matter was clearly evident. Cell changes were present in both dorsal and ventral horns and were most marked on the ipsilateral side compared to the contralateral cord. Nerve cell and glial cell changes are normally present in the regions showing intense albumin immunoreactivity, indicating disruption of the blood-spinal cord barrier (BSCB). Our observations indicate that a chronic nerve lesion has the capacity to induce selective breakdown of the BSCB that could be responsible for activation of astrocytes and abnormal cell reaction. These findings enhance our understanding of the pathophysiology of neuropathic pain and/or other spinal cord disorders.

Adaptation, Physiological↗
PubMed2006

Whole-body hyperthermia in the rat disrupts the blood-cerebrospinal fluid barrier and induces brain edema.

The present investigation was undertaken to find out whether whole-body hyperthermia (WBH) alters blood-cerebrospinal fluid barrier (BCSFB) permeability to exogenously-administered tracers and whether choroid plexus and ependymal cells exhibit morphological alterations in hyperthermia. Rats subjected to 4 hours of heat stress at 38 degrees C in a biological oxygen demand (BOD) incubator exhibited a profound increase in the BCSFB to Evans blue and radioiodine. Blue staining of the dorsal surface of the hippocampus and caudate nucleus and a significant increase in Evans blue and [131]Iodine in cisternal cerebrospinal fluid were seen following 4-hour heat stress compared to control. Degeneration of choroidal epithelial cells and underlying ependyma, a dilated ventricular space, and degenerative changes in the underlying neuropil were frequent. Hippocampus, caudate nucleus, thalamus, and hypothalamus exhibited profound increases in water content after 4 hours of heat stress. These observations suggest that hyperthermia induced by WBH is capable of breaking down the BCSFB and contributing to cell and tissue injury in the central nervous system.

Animals↗
PubMed2006

Atrial natriuretic peptide: its putative role in modulating the choroid plexus-CSF system for intracranial pressure regulation.

Evidence continues to build for the role of atrial natriuretic peptide (ANP) in reducing cerebrospinal fluid (CSF) formation rate, and thus, intracranial pressure. ANP binds to choroid plexus (CP) epithelial cells. This generates cGMP, which leads to altered ion transport and the slowing of CSF production. Binding sites for ANP in CP are plentiful and demonstrate plasticity in fluid imbalance disorders; however, specific ANP receptors in epithelial cells need confirmation. Using antibodies directed against NPR-A and NPR-B, we now demonstrate immunostaining not only in the choroidal epithelium (including cytoplasm), but also in the ependyma and some endothelial cells of cerebral microvessels in adult rats (Sprague-Dawley). The choroidal and ependymal cells stained almost universally, thus substantiating the initial autoradiographic binding studies with 125I-ANP. Because ANP titers in human CSF have previously been shown to increase proportionally to increments in ICP, we propose a compensatory ANP modulation of CP function to down-regulate ICP in hydrocephalus. Further evidence for this notion comes from the current finding of increased frequency of "dark" epithelial cells in CP of hydrocephalic (HTx) rats, which fits our earlier observation that the "dark" choroidal cells, associated with states of reduced CSF formation, are increased by elevated ANP in CSF. Altogether, ANP neuroendocrine-like regulation at CSF transport interfaces and blood-brain barrier impacts brain fluid homeostasis.

Animals↗
PubMed2006

Neuroprotective effects of melanocortins in experimental spinal cord injury. An experimental study in the rat using topical application of compounds with varying affinity to melanocortin receptors.

The possibility that local administration of low molecular weight non-peptide compounds with varying affinities at melanocortin receptors in the spinal cord will influence pathophysiological outcome of spinal cord injury (SCI) was examined in a rat model. Five new Melacure compounds ME10092, ME10354, ME10393, ME10431 and ME10501 were used in this investigation. Each compound was dissolved in saline and tested at 3 different doses, i.e. 1 microg, 5 microg and 10 microg total dose in 10 microl applied topically 5 min after SCI. The animals were allowed to survive 5 h and trauma induced edema formation, breakdown of the blood-spinal cord barrier (BSCB) and cell injuries were examined and compared with untreated injured rats. A focal SCI inflicted by an incision into the right dorsal horn of the T10-11 segments resulted in marked edema formation, breakdown of the BSCB to Evans blue albumin and caused profound nerve cell injury in the T9 and the T12 segments. Topical application of ME10501 (a compound with high affinity at melanocortin, MC-4 receptors) in high doses (10 microg) resulted in most marked neuroprotection in the perifocal spinal cord (T9 and T12) segments. On the other hand, only a mild or no effect on spinal cord pathology was observed in the traumatized animals that received ME10092, ME10354, ME10393 and ME10431 at 3 different doses. These observations suggest that non-peptide compounds with varying affinity to melanocortin receptors are able to influence the pathophysiology of SCI. Furthermore, compounds acting at melanocortin, MCR4 receptors are capable to induce neuroprotection in spinal cord following trauma.

Administration, Topical↗
PubMed2006

Spinal cord injury induced heat shock protein expression is reduced by an antioxidant compound H-290/51. An experimental study using light and electron microscopy in the rat.

The possibility that oxidative stress participates in heat shock protein 72 kD (HSP 72) expression following a focal trauma to the spinal cord was examined using a potent antioxidant compound H-290/51 in a rat model. A focal spinal cord injury (SCI) inflicted by making a longitudinal incision on the right dorsal horn of the T10-T11 segment under equithesin anaesthesia resulted in profound upregulation of HSP 72 expression in the adjacent spinal cord segments T9 and T12. This expression of HSP was most marked in the ipsilateral cord at 5 h after SCI. Pretreatment with H-290/51 (50 mg/kg, p.o.) 30 min before SCI markedly attenuated HSP expression in the spinal cord seen at 5 h. The motor functions of traumatized rats were also improved in the drug treated group. At this time, structural changes in the spinal cord and edema formation were considerable reduced compared to the untreated traumatized rats. Taken together, these observations suggest that (i) oxidative stress participates in HSP response following trauma, and (ii) the antioxidant compound H-290/51 attenuates cellularstress, improves motor functions and induces considerable neuroprotection in the early phase of SCI. Further studies using post-injury treatment with H-290/51 is needed to explore its therapeutic potentials in clinical settings.

Animals↗
PubMed2006

Hyperthermia influences excitatory and inhibitory amino acid neurotransmitters in the central nervous system. An experimental study in the rat using behavioural, biochemical, pharmacological, and morphological approaches.

Role of excitatory amino acids, glutamate, aspartate, and inhibitory amino acids, gamma aminobutyric acid (GABA) and glycine in brain damage caused by heat stress was examined in a rat model. Subjection of rats to 4 h heat stress at 38 degrees C in a biological oxygen demand (BOD) incubator resulted in a marked increase in glutamate and aspartate in some brain regions, whereas a significant decline in GABA and glycine was observed in several brain areas. Profound behavioural alterations and impairment of motor and cognitive functions were seen at this time. Breakdown of the blood-brain barrier (BBB), reduction in regional cerebral blood flow (CBF), edema formation and cell injuries are prominent in several parts of the brain. Pretreatment with multiple opioid receptor antagonist, naloxone (10 mg/kg, i.p.) significantly restored the heat stress induced decline in GABA and glycine and thwarted the elevation of glutamate and aspartate in various brain areas. The motor or cognitive deficits were also attenuated. A significant reduction in BBB permeability, cerebral blood flow abnormalities, edema formation and cell injuries was evident. These novel observations suggest that (i) glutamate, aspartate, GABA and glycine are involved in the pathophysiology of heat stress, and (ii) a balance between excitatory and inhibitory amino acids in brain is crucial in hyperthermia induced brain injuries or repair.

Animals↗
PubMed2005

Enhanced bronchial expression of vascular endothelial growth factor and receptors (Flk-1 and Flt-1) in patients with chronic obstructive pulmonary disease.

BACKGROUND: Ongoing inflammatory processes resulting in airway and vascular remodelling characterise chronic obstructive pulmonary disease (COPD). Vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1) could play a role in tissue remodelling and angiogenesis in COPD. METHODS: The cellular expression pattern of VEGF, Flt-1, and KDR/Flk-1 was examined by immunohistochemistry in central and peripheral lung tissues obtained from ex-smokers with COPD (forced expiratory volume in 1 second (FEV(1)) <75% predicted; n = 14) or without COPD (FEV(1) >85% predicted; n = 14). The immunohistochemical staining of each molecule was quantified using a visual scoring method with grades ranging from 0 (no) to 3 (intense). RESULTS: VEGF, Flt-1, and KDR/Flk-1 immunostaining was localised in vascular and airway smooth muscle (VSM and ASM) cells, bronchial, bronchiolar and alveolar epithelium, and macrophages. Pulmonary endothelial cells expressed Flt-1 and KDR/Flk-1 abundantly but not VEGF. Bronchial VEGF expression was higher in microvascular VSM cells and ASM cells of patients with COPD than in patients without COPD (1.7 and 1.6-fold, p<0.01, respectively). VEGF expression in intimal and medial VSM (1.7 and 1.3-fold, p<0.05) of peripheral pulmonary arteries associated with the bronchiolar airways was more intense in COPD, as was VEGF expression in the small pulmonary vessels in the alveolar region (1.5 and 1.7-fold, p<0.02). In patients with COPD, KDR/Flk-1 expression was enhanced in endothelial cells and in intimal and medial VSM (1.3, 1.9 and 1.5-fold, p<0.02) while endothelial Flt-1 expression was 1.7 times higher (p<0.03). VEGF expression was significantly increased in bronchiolar and alveolar epithelium as well as in bronchiolar macrophages (1.5-fold, p<0.001). The expression of VEGF in bronchial VSM and mucosal microvessels as well as bronchiolar epithelium was inversely correlated with FEV(1) (r<-0.45; p<0.01). CONCLUSIONS: VEGF and its receptors Flt-1 and KDR/Flk-1 may be involved in peripheral vascular and airway remodelling processes in an autocrine and/or paracrine manner. This system may also be associated with epithelial cell viability during airway wall remodelling in COPD.

Bronchi↗
PubMed2005

Proinflammatory cytokines upregulate mRNA expression and secretion of vascular endothelial growth factor in cultured human airway smooth muscle cells.

Airflow obstruction in chronic airway disease is associated with airway and pulmonary vascular remodeling, of which the molecular mechanisms are poorly understood. Paracrine actions of angiogenic factors released by resident or infiltrating inflammatory cells following activation by proinflammatory cytokines in diseased airways could play a major role in the airway vascular remodeling process. Here, the proinflammatory cytokines interleukin (IL)-1beta, and tumor necrosis factor (TNF)-alpha were investigated on cell cultures of human airway smooth muscle (ASM) for their effects on mRNA induction and protein release of the angiogenic peptide, vascular endothelial growth factor (VEGF). IL-1beta (0.5 ng/mL) and TNF-alpha (10 ng/mL) each increased VEGF mRNA (3.9 and 1.7 kb) expression in human ASM cells, reaching maximal levels between 16 and 24 and 4 and 8 h, respectively. Both cytokines also induced a time-dependent release of VEGF, which was not associated with increased ASM growth. Preincubation of cells with 1 microM dexamethasone abolished enhanced release of VEGF by TNF-alpha. The data suggest that human ASM cells express and secrete VEGF in response to proinflammatory cytokines and may participate in paracrine inflammatory mechanisms of vascular remodeling in chronic airway disease.

Bronchi↗
PubMed2003

Antioxidant compounds EGB-761 and BN-52021 attenuate brain edema formation and hemeoxygenase expression following hyperthermic brain injury in the rat.

Role of carbon monoxide (CO) in hyperthermic brain injury induced brain pathology was examined in a rat model using immunohistochemistry of the hemeoxygenase-2 (HO-2) enzyme. Exposure of rats to 4 h heat stress at 38 degrees C resulted in profound hyperthermia, breakdown of the blood-brain barrier (BBB), brain edema formation, cell damage and expression of HO-2 in several brain regions. Pretreatment with potent antioxidant compounds EGB-761 and BN-52021 markedly reduced the HO-2 expression, BBB breakdown, brain edema formation and cell damage without attenuating the hyperthermic response. This effect was most marked in animals treated with EGB-761. These observations suggest that upregulation of HO-2 representing generation of CO plays important roles in hyperthermic brain injury, and oxidative stress seems to be one of the most important signals in inducing HO-2 expression in hyperthermia, not reported earlier.

Animals↗
PubMed2003

Neurotrophic factors attenuate microvascular permeability disturbances and axonal injury following trauma to the rat spinal cord.

Alterations of the blood-spinal cord barrier (BSCB) following spinal cord injury (SCI) and leakage of serum proteins induce vasogenic edema and cell damage. The possibility that two members of the neurotrophin family, BDNF or IGF-1 induce neuroprotection by attenuating the BSCB permeability following trauma was examined in a rat model. Repeated topical application of BDNF or IGF-1 (0.1 1microg, 0.5 microg or 1 microg in 10 microl) onto the spinal cord 30 min before SCI or 2, 5, 10 or 30 min thereafter significantly attenuated BSCB permeability to Evans blue and iodine. In the neurotrophin treated rats. edema formation, degradation of MBP, and myelin vesiculation were much less frequent compared to the untreated traumatised rats. The protective effect of BDNF and IGF-1 was most pronounced at the high dose (1 microg in 10 microl) given either 30 min before or within 10 min after SCI. The observations suggest that early intervention with neurotrophins in high doses following trauma (within 10 min) attenuates disturbances of the fluid microenvironment of the spinal cord. This indicates that BSCB opening plays an important role in SCI induced myelin vesiculation and cord pathology.

Animals↗
PubMed2003

Depletion of endogenous serotonin synthesis with p-CPA attenuates upregulation of constitutive isoform of heme oxygenase-2 expression, edema formation and cell injury following a focal trauma to the rat spinal cord.

The possibility that the upregulation of hemeoxygenase (HO) enzyme responsible for carbon monoxide (CO) formation in the spinal cord following trauma is involved in edema formation and cell damage was examined in a rat model. A focal trauma to the rat spinal cord by making an incision into the right dorsal horn of the T10-11 segment resulted in profound upregulation of HO-2 (the constitutive isoform of the enzyme) expression in the T9 and T12 segments 5 h after injury. In these segments a marked increase in edema formation, nerve cell damage, and expression of heat shock protein (HSP 72) were observed. Pretreatment with p-chlorophenylalanine (p-CPA, a serotonin synthesis inhibitor) significantly attenuated the trauma induced edema formation, cell injury, and HSP expression. Upregulation of HO-2 in p-CPA treated traumatised rats was considerably reduced. These observations suggest that (i) spinal cord injury has the capacity to induce an upregulation of HO-2 and HSP expression, (ii) abnormal production of CO as reflected by HO-2 expression is injurious to the cord, and (iii) that endogenous serotonin is involved in HO-2 expression in the cord.

Animals↗
PubMed2003

Low molecular weight compounds with affinity to melanocortin receptors exert neuroprotection in spinal cord injury--an experimental study in the rat.

The possibility that five new low molecular weight compounds with varying affinity and selectivity to the melanocortin receptors will exert neuroprotective effects in the spinal cord injury (SCI) induced edema formation and cell damage was examined in a rat model. A focal trauma of the rat spinal cord made by an incision into the right dorsal horn (T10-11) resulted in profound edema formation, leakage of Evans blue albumin and cell injury of the T9 segment at 5 h. Topical application of the Melacure compound ME10501 in high doses (10 microg in 10 microl) given 5 min after SCI resulted in most significant neuroprotection of the T9 segment of the cord compared to other compounds. Thus, marked reduction in water content, leakage of Evans blue albumin, and cell injury were observed in ME10501 treated traumatised rats. These observations suggest that the non-peptide compound ME10501 with affinity to the melanocortin receptor MC4 is capable to induce neuroprotection in the spinal cord following trauma not reported earlier.

Animals↗