MRI analysis of the changes in apparent water diffusion coefficient, T(2) relaxation time, and cerebral blood flow and volume in the temporal evolution of cerebral infarction following permanent middle cerebral artery occlusion in rats

Detailed knowledge of similarities and differences between animal models and human stroke is decisive for selecting clinically effective drugs based on efficacy data obtained preclinically. Differences in the temporal evolution of stroke pathologies between animal models and man have been reported. In view of the importance of this issue for the development of neuroprotective treatments, the temporal evolution of stroke pathologies in the rat permanent middle cerebral artery occlusion (pMCAO) model has been evaluated with magnetic resonance imaging modalities under experimental conditions matching as close as possible those used in humans. Changes in the ipsilateral and contralateral cortex and striatum of cerebral blood flow (CBF) and volume (CBV), apparent diffusion coefficient (ADC), and spin-spin relaxation time (T(2)), as well as total cortical and striatal infarct volumes, calculated from CBF, ADC, and T(2) maps, were determined starting 1 h up to 216 h post-pMCAO. The temporal evolution of the MRI parameters in this rat model was similar to that observed in humans. In particular, the ADC values were decreased for more than 3 days and returned back to baseline between 4 to 8 days, to increase by day 9 only. Thus the stroke pathology in this rat model develops at a similar pace as in stroke patients arguing against a fundamental difference in the mechanisms involved. The infarct volumes however develop differently in this rat model as they invariably increase over the first 48 h, while in humans the evolution of infarct volume is slower and more heterogeneous.     

Safety and efficacy of a multicenter study using intraarterial chemotherapy in conjunction with osmotic opening of the blood-brain barrier for the treatment of patients with malignant brain tumors

BACKGROUND: The aim of this study was to determine the safety and efficacy of intraarterial chemotherapy with osmotic opening of the blood-brain barrier (BBB) for the treatment of malignant brain tumors when administered across multiple centers. METHODS: Patients with primary central nervous system lymphoma (PCNSL), primitive neuroectodermal tumor (PNET), germ cell tumor, cancer metastasis to the brain, or low or high grade glioma were eligible. Prior to entry, magnetic resonance imaging or computed tomography brain scan, medical history, neurologic status, and Karnofsky performance status were reviewed at the coordinating center. Standardized anesthesia and intraarterial catheterization guidelines were followed by a multidisciplinary team at each center. Between March 1994 and November 1997, 5 universities treated 221 adult patients with intraarterial chemotherapy with or without osmotic opening of the BBB (2464 procedures). RESULTS: Of evaluable patients with PCNSL, 40 of 53 (75%) achieved complete response (CR). All evaluable patients with PNET (n = 17), metastatic disease (n = 12), or germ cell tumor (n = 4) achieved stable disease (SD) or better. Of 57 evaluable patients with glioblastoma multiforme, 45 (79%) achieved SD or better. Asymptomatic subintimal tear occurred in 11 of 221 patients (5%), pulmonary embolism in 6 of 221 (2.7%), and renal toxicity in 4 of 221 (1.8%). One patient with extensive glioma expired within 48 hours after treatment. CONCLUSIONS: Using standard guidelines and protocols, intraarterial chemotherapy with or without osmotic opening of the BBB is feasible across multiple centers with a low incidence of catheter-related complications. In patients with chemotherapy-sensitive tumors, such as PCNSL, PNET, germ cell tumor, and cancer metastasis to the central nervous system, enhanced delivery results in a high degree of tumor response, with an efficacy profile that is reproducible across multiple centers.     

Induced chorioretinal venous anastomosis in experimental retinal branch vein occlusion.

Iatrogenic retinal vein to choroidal vein anastomoses were created using laser photocoagulation in six of seven dog eyes in which a partial branch retinal vein occlusion had previously been created photochemically. A similar attempt to create an anastomosis was made in six control eyes in which no branch vein occlusion was present. In the eyes in which a branch retinal vein had been created, a venous chorioretinal anastomosis appeared to be present by 3 to 6 weeks. In three control eyes similar venous anastomosis was created; however this took 6 to 8 weeks to develop and was of much smaller calibre than the one that developed in the presence of a partial branch retinal vein occlusion. No adverse complications were noted in the period of the study (3 months). This study demonstrates that chorioretinal venous anastomoses can be created and may be of use in the treatment of partial retinal vein occlusions that show signs of progression.     

Genetic knockout and pharmacological blockade studies of the 5-HT7 receptor suggest therapeutic potential in depression

The affinity of several antidepressant and antipsychotic drugs for the 5-HT7 receptor and its CNS distribution suggest potential in the treatment of psychiatric diseases. However, there is little direct evidence of receptor function in vivo to support this. We therefore evaluated 5-HT7 receptors as a potential drug target by generating and assessing a 5-HT7 receptor knockout mouse. No difference in assays sensitive to potential psychotic or anxiety states was observed between the 5-HT7 receptor knockout mice and wild type controls. However, in the Porsolt swim test, 5-HT7 receptor knockout mice showed a significant decrease in immobility compared to controls, a phenotype similar to antidepressant treated mice. Intriguingly, treatment of wild types with SB-258719, a selective 5-HT7 receptor antagonist, did not produce a significant decrease in immobility unless animals were tested in the dark (or active) cycle, rather than the light, adding to the body of evidence suggesting a circadian influence on receptor function. Extracellular recordings from hypothalamic slices showed that circadian rhythm phase shifts to 8-OH-DPAT are attenuated in the 5-HT7 receptor KO mice also indicating a role for the receptor in the regulation of circadian rhythms. These pharmacological and genetic knockout studies provide the first direct evidence that 5-HT7 receptor antagonists should be investigated for efficacy in the treatment of depression.