dizocilpine-maleate and Carotid-Artery-Diseases

Most therapeutic agents are administered intravenously (IV) in clinical settings and intraperitoneally (IP) in preclinical studies with neonatal rodents; however, it remains unclear whether intraperitoneal (IP) injection is truly an acceptable alternative for intravenous (IV) injection in preclinical studies. The objective of our study is to clarify the differences in the therapeutic effects of drugs and in the distribution of infused cells after an IP or IV injection in animals with brain injury.. Dexamethasone or MK-801, an N-methyl-d-aspartate receptor antagonist was administered either IP or IV in a mouse model of neonatal hypoxic-ischemic encephalopathy. Green fluorescent protein-expressing mesenchymal stem cells (MSCs) or mononuclear cells (MNCs) were injected IP or IV in the mouse model. Two hours and 24h after the administration of the cells, we investigated the cell distributions by immunohistochemical staining. We also investigated distribution of IV administered MNCs labeled with 2-[18F]fluoro-2-deoxy-d-glucose in a juvenile primate, a macaque with stroke 1h after the administration.. IP and IV administration of dexamethasone attenuated the brain injury to a similar degree. IP administration of MK-801 attenuated brain injury, whereas IV administration of MK-801 did not. The IV group showed a significantly greater number of infused cells in the lungs and brains in the MSC cohort and in the spleen, liver, and lung in the MNC cohort compared to the IP group. In the macaque, MNCs were detected in the spleen and liver in large amounts, but not in the brain and lungs.. This study demonstrated that the administration route influences the effects of drugs and cell distribution. Therefore, a preclinical study may need to be performed using the optimal administration route used in a clinical setting.

Topics: Animals; Animals, Newborn; Bone Marrow Transplantation; Brain; Carotid Artery Diseases; Dexamethasone; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Femoral Vein; Fluorodeoxyglucose F18; Hypoxia-Ischemia, Brain; Injections, Intraperitoneal; Injections, Intravenous; Leukocytes, Mononuclear; Macaca; Male; Mice; Neuroprotective Agents; Random Allocation; Rats, Inbred Lew; Rats, Transgenic; Treatment Outcome

1. The purpose of the present study was to investigate the effect of bilateral common carotid artery occlusion (BCCAO) on cardiovascular responses and nitric oxide (NO) formation in the nucleus tractus solitarius (NTS). 2. Twenty-three adult cats were anaesthetized intraperitoneally with urethane (400 mg/kg) and alpha-chloralose (40 mg/kg). The femoral artery was cannulated to allow monitoring of systemic arterial pressure (SAP) and heart rate (HR). The femoral vein was cannulated for intravenous drug administration. 3. Extracellular NO levels in the NTS were measured by in vivo voltammetry using an NO microsensor combined with a microcomputer-controlled apparatus. 4. Microinjection of l-arginine (30 nmol) into the NTS produced hypotension and NO release. This effect of l-arginine was not changed by 2 min of BCCAO. 5. Bilateral common carotid artery occlusion produced increases in SAP and NO levels. These effects were more apparent in vagotomized than in intact animals. 6. The onset latency of BCCAO-induced changes in SAP levels (8.4 +/- 2.5 s) was longer than that for changes in NO (4.7 +/- 1.7 s). 7. Bilateral common carotid artery occlusion induced hypertension and NO release in the NTS of intact and vagotomized animals. These cardiovascular and NO responses to BCCAO were significantly attenuated by NG-nitro-l-arginine methyl ester (10 mg/kg, i.v.) and MK-801 (2.5 mg/kg, i.v.). These data suggest that NO synthase and activation of N-methyl-d-aspartate receptors are involved in the cardiovascular and NO responses to BCCAO.

Topics: Animals; Arterial Occlusive Diseases; Blood Pressure; Carotid Artery Diseases; Carotid Artery, Common; Cats; Dizocilpine Maleate; Female; Hypertension; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Receptors, N-Methyl-D-Aspartate; Solitary Nucleus; Time Factors

1. The effect of a novel, highly potent and selective kappa-opioid receptor agonist, GR89696, has been evaluated in two animal models of cerebral ischaemia: transient bilateral carotid artery occlusion in the Mongolian gerbil and permanent, unilateral middle cerebral artery occlusion in the mouse. 2. In the Mongolian gerbil model, administration of GR89696 (3 to 30 micrograms kg-1, s.c.), immediately before and at 4 h after insult, produced a dose-dependent reduction in the hippocampal CA1 neuronal cell loss resulting from a 7-min bilateral carotid occlusion. Similar effects were obtained with two other kappa-agonists, GR86014 (1 mgkg-1, s.c.) and GR91272 (1 mgkg-1, s.c.). The neuroprotective effect of GR89696 was completely blocked by prior administration of the opioid receptor antagonist, naltrexone, at 10 mgkg-1, s.c. Repeated post-treatment with GR89696 (100 micrograms kg-1, s.c.) or GR44821 (10 mgkg-1, s.c.) was also effective in protecting completely the hippocampal CA1 neurones from ischaemia-induced neurodegeneration. 3. In the permanent, unilateral middle cerebral artery occlusion model in the mouse, repeated administration of GR89696 at 300 micrograms kg-1, s.c. produced a 50% reduction in cerebrocortical infarct volume. In these experiments GR89696 was dosed 5 min, 4, 8, 12, 16, 20 and 24 h after occlusion on the first day and then three times daily for the next three days. GR89696 (300 micrograms kg-1) also produced a significant 35% reduction in infarct volume in this model when the initiation of dosing was delayed for 6 h after the insult. 4. The results indicate that the potent kappa-opioid receptor agonist, GR89696, is neuroprotective in both global and focal cerebral ischaemia models and suggest that, with this class of compound, there may be a considerable time window for pharmacological intervention.

Topics: Animals; Brain Ischemia; Carotid Artery Diseases; Dizocilpine Maleate; Dose-Response Relationship, Drug; Female; Gerbillinae; Male; Mice; Nervous System Diseases; Piperazines; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa

The neuroprotective effects of MK-801, a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, were evaluated in models of cerebral ischemia using Mongolian gerbils. Bilateral occlusion of the carotid arteries for a period of 5 min resulted in a consistent pattern of degeneration of hippocampal CA1 and CA2 pyramidal neurons, which was quantified using an image analyzer. Systemic administration of MK-801 (0.01-10 mg/kg, i.p.) 1 hr prior to the occlusion caused a dose-dependent protection of the CA1 and CA2 neurons. The ED50 value for neuroprotection by MK-801 was calculated to be 0.3 mg/kg, and at doses greater than or equal to 3 mg/kg the majority of animals were completely protected against the ischemic insult. Systemic administration of MK-801 (1 or 10 mg/kg, i.p.) 1 hr prior to unilateral occlusion of the right carotid artery resulted in significant protection against hippocampal neurodegeneration following 10 min of occlusion, and increased the survival rate after 30 min of occlusion. The potent neuroprotective effects of MK-801 in these cerebral ischemia models add further weight to the evidence that NMDA receptors are involved in the mechanism of ischemia-induced neuronal degeneration.

Topics: Animals; Arterial Occlusive Diseases; Brain Ischemia; Carotid Artery Diseases; Dibenzocycloheptenes; Dizocilpine Maleate; Female; Gerbillinae; Hippocampus; Male; Nerve Degeneration