Biomedical subjects

Hari Shanker Sharma

Publications and source records attributed to Hari Shanker Sharma.

8 recordsLinked to original sources

PubMed2006

Spinal nerve lesion alters blood-spinal cord barrier function and activates astrocytes in the rat.

Alterations in the spinal cord microenvironment in a neuropathic pain model in rats comprising right L-4 spinal nerve lesion were examined following 1, 2, 4 and 10 weeks using albumin and glial fibrillary acidic protein (GFAP) immunoreactivity. Rats subjected to nerve lesion showed pronounced activation of GFAP indicating astrocyte activation, and exhibited marked leakage of albumin, suggesting defects of the blood-spinal cord barrier (BSCB) function in the corresponding spinal cord segment. The intensities of these changes were most prominent in the gray matter of the lesioned side compared to the contralateral cord in both the dorsal and ventral horns. The most marked changes in albumin and GFAP immunoreaction were seen after 2 weeks and persisted with mild intensities even after 10 weeks. Distortion of nerve cells, loss of neurons and general sponginess were evident in the gray matter of the spinal cord corresponding to the lesion side. These nerve cell and glial cell changes was mainly evident in the areas showing leakage of endogenous albumin in the spinal cord. These novel observations indicate that chronic nerve lesion has the capacity to induce a selective increase in local BSCB permeability that could be instrumental in nerve cell and glial cell activation. These findings may be relevant to our current understanding on the pathophysiology of neuropathic pain.

Albumins↗

PubMed2006

Alterations in blood-brain barrier function by morphine and methamphetamine.

The possibility that stress associated with morphine and amphetamine administration or withdrawal will influence the blood-brain barrier (BBB) and brain dysfunction was examined in a rodent model. Repeated daily administration of morphine (10 mg/kg, i.p.) resulted in drug dependence in rats on the sixth day and onwards. Measurement of the BBB permeability to large molecule tracers normally bound to proteins, e.g., Evans blue albumin and radioiodine (([131])Iodine) did not show any leakage on the 12th day of drug dependence. On the other hand, spontaneous withdrawal of morphine on day 1 resulted in profound stress symptoms. These symptoms were much more intense on the second day of morphine withdrawal. Alterations in the BBB to protein tracers were seen in several regions of the brain. This increase in BBB to protein tracers was most pronounced on the second day of morphine withdrawal. These rats also exhibited abnormal neuronal, glial and stress protein, the heat-shock protein 72 kD (HSP-72 kD) response. On the other hand, acute administration of methamphetamine (40 mg/kg, i.p.) in mice resulted in marked extravasation of endogenous serum protein as seen with increased expression of albumin immunohistochemistry. These observations suggest that psychostimulants and associated stress are capable to influence the brain function, probably through modifying the BBB function, not reported earlier.

Analgesia↗

PubMed2006

Hyperthermia induced brain oedema: current status and future perspectives.

Recent years have witnessed a large number of deaths due to hyperthermia and heat-related illnesses across the globe in human population resulting in great social and medical problems. The detailed mechanisms and probable therapeutic measures have still not been worked out. Sporadic autopsy reports show profound brain swelling leading to compression of vital centers that could be responsible for instant death. Increased permeability of the blood-brain barrier (BBB) and brain swelling is also seen in experimental models of heat stress. It appears that hyperthermia is instrumental in opening of the BBB either directly or indirectly leading to vasogenic oedema formation, a feature crucial to molecular and cellular alteration in the brain inducing cell and tissue injury. The probable mechanisms and functional significance of heat induced brain oedema and BBB damage in relation to neurodegenerative changes are discussed.

Animals↗

PubMed2005

Neuroprotective effects of neurotrophins and melanocortins in spinal cord injury: an experimental study in the rat using pharmacological and morphological approaches.

Spinal cord injury (SCI) induces lifetime disability, and no suitable therapy is available to treat victims or to minimze their sufferings. Recently, neurotrophins and compounds acting at melanocortin receptors have been been identified as potential neuroprotective agents. In this investigation, the neuroprotective effects of neurotrophins and melanocortins on the pathophysiology of SCI were examined in a rat model. The SCI was produced by making a longitudinal incision into the right dorsal horn of the T10-11 segments under equithesin anesthesia. In separate groups, neurotrophins [BDNF or IGF-1 (0.1-1 microg/10 microL in saline)] or melanocortins (ME10092, ME10354, ME10393, ME10431, and ME10501, having affinities to melanocortin receptors; 1-10 mug in saline) were applied topically over the traumatized cord segment within 5-10 min after SCI and the rats were allowed to survive for 5 h. A focal SCI resulted in widespread disruption of the blood-spinal cord barrier (BSCB) to Evans blue albumin (EBA), ([131])iodine, or lanthanum tracers and exhibited profound edema formation and cell or tissue destruction. Topical application of BDNF, IGF-1, or ME10501 (having high affinity to melanocortin-4 receptor, MCR-4) in high quantity markedly attenuated BSCB disruption, edema formation, and nerve cell, glial cell, and axonal injuries. On the other hand, low doses of neurotrophins or melanocortins were not effective in attenuating pathophysiology of SCI. These observations suggest that neurotrophins (BDNF and IGF-1) and melanocortins (with high affinity to MCR-4) are capable of inducing neuroprotection if applied shortly after trauma in high doses. Taken together, the results indicate that neurotrophins and melanocortins participate in the pathophysiology of spinal cord cell and tissue injury following trauma.

Animals↗

PubMed2005

Neuroprotective effects of nitric oxide synthase inhibitors in spinal cord injury-induced pathophysiology and motor functions: an experimental study in the rat.

The role of nitric oxide (NO) in spinal cord injury (SCI)-induced motor dysfunction, breakdown of the blood-spinal cord barrier (BSCB), edema formation, and cell injury was examined using a pharmacological approach. We used three types of nitric oxide synthase (NOS) inhibitors: a nonselective blocker, L-NAME; an irreversible inhibitor of all isoforms of NOS, L-NMMA; and a long-term competitive inhibitor of neuronal NOS with equal potency to inhibit endothelial NOS, L-NNA. The compounds were administered once daily in separate groups of rats for 7 days. On the 8th day, SCI was performed by making a longitudinal incision into the right dorsal horn of the T10-11 segments, and the rats were allowed to survive 5 h after injury. Long-term treatment with L-NNA attenuated SCI-induced NOS upregulation, BSCB breakdown, edema formation, and cell injury, whereas comparatively less neuroprotection is offered by L-NMMA. The magnitude of neuroprotection is much less evident in injured animals that received L-NAME. Interestingly, SCI-induced motor dysfunction measured according to the Tarlov scale showed close correlation with the magnitude of neuroprotection. Thus, an improvement in motor function was seen in animals pretreated with L-NNA, whereas rats treated with L-NAME or L-NMMA did not show any influence on motor dysfunction after SCI. This observation suggests that inhibition of neuronal NOS is important for neuroprotection, and the disturbances in motor function following SCI are associated with the state of spinal cord pathology.

Animals↗

PubMed2005

Circulatory arrest as a model for studies of global ischemic injury and neuroprotection.

Despite many programs aimed at better immediate care of cardiac arrest victims, the subsequent mortality rate is high, with myocardial and central nervous system (CNS) injuries as the most common causes of death. Preclinical research is badly needed to produce a sound base for future clinical trials and possible improvements in clinical outcome. In our laboratory, we use piglets weighing approximately 25 kg. Ventricular fibrillation is produced by an AC current and left without treatment for 8-12 min, after which cardiopulmonary resuscitation according to current human guidelines is undertaken. The heart is then defibrillated and restoration of spontaneous circulation induced. During the procedure, blood pressure and flow measurements are obtained in the systemic, pulmonary, and cerebral circulation. Peroxidation and inflammation are monitored by systemic and cerebral venous plasma concentrations of isoprostane (8-iso-PGF(2alpha)), an indicator of oxidative damage, and prostaglandin F(2alpha) metabolite (15-keto-dihydro-PGF(2alpha)), an indicator of cyclooxygenase-2 activity, respectively. Neurocellular damage is monitored by the jugular plasma concentration of protein S-100beta. Neurological outcome is assessed at >24 h after the incident. Our results show that plasma concentrations of 8-iso-PGF(2alpha) are greater after more extended periods of ischemia. PBN (alpha-phenyl-N-tert-butyl nitrone), a so-called spin-trap scavenger, has a neuroprotective effect since neurological outcome is enhanced, and the 8-iso-PGF(2alpha) concentration is decreased during reperfusion. Use of water-soluble sulfonated PBN (S-PBN) results in better autoregulation of cerebral cortical blood flow and less peroxidation of CNS lipids during reperfusion. These observations suggest that our model can be used to explore neuroprotective effects of potential therapeutic agents.

Animals↗

PubMed2005

Pathophysiology of blood-spinal cord barrier in traumatic injury and repair.

Blood-spinal cord barrier (BSCB) plays an important role in the regulation of the fluid microenvironment of the spinal cord. Trauma to the spinal cord impairs the BSCB permeability to proteins leading to vasogenic edema formation. Several endogenous neurochemical mediators and growth factors contribute to trauma induced BSCB disruption. Studies carried out in our laboratory suggest that those drugs and neurotrophic factors capable to attenuate the BSCB dysfunction following trauma are neuroprotective in nature. Whereas, agents that do not exert any influence on the BSCB disruption failed to reduce cell injury. These observations are in line with the idea that BSCB disruption plays an important role in the pathophysiology of spinal cord injuries. The probable mechanism(s) of trauma induced BSCB dysfunction and its contribution to cell injuries are discussed.

Animals↗

PubMed2002

Assessment of spinal cord pathology following trauma using early changes in the spinal cord evoked potentials: a pharmacological and morphological study in the rat.

The possibility that spinal cord pathology following trauma can be assessed with early changes in the spinal cord evoked potentials (SCEPs) was examined in a rat model. Spinal cord injury (SCI) was produced in Equithesin-anesthetized (3 ml/kg, i.p.) rats through a longitudinal incision into the right dorsal horn at the T10-11 segments. The SCEPs were recorded with epidural electrodes placed over the T9 (rostral) segment of the cord. The SCEPs consisted of a small positive amplitude and a broad and high negative amplitude (NA). SCI resulted in an instant depression of the rostral NA that lasted for 1 h. However, the latency of NA continued to increase over time. At 5 h, spinal cord blood flow declined by 30% in the T9 segment, whereas the spinal cord water content and the permeability of the blood-spinal cord barrier (BSCB) were markedly increased. Damage to the nerve cells, glial cells, and myelin was quite common in the spinal cord, as seen by light and electron microscopy. Pretreatment with p-chlorophenylalanine, indomethacin, ibuprofen, and nimodipine attenuated the SCEP changes immediately after trauma and resulted in a marked reduction in edema formation, BSCB permeability, and blood flow changes at 5 h. However, pretreatment with cyproheptadine, dexamethasone, phentolamine, and propranolol failed to attenuate the SCEP changes after SCI and did not reduce the cord pathology. These observations suggest that early changes in SCEP reflect secondary injury-induced alterations in the cord microenvironment. Obviously, these changes are crucial in determining the ultimate magnitude and severity of cord pathology.

Adrenergic alpha-Antagonists↗