Hostname: page-component-76fb5796d-45l2p Total loading time: 0 Render date: 2024-04-26T03:22:46.779Z Has data issue: false hasContentIssue false
  • English
  • Français

A Blood-Brain Barrier Disruption Model Eliminating the Hemodynamic Effect of Ketamine

Published online by Cambridge University Press:  16 February 2016

David Fortin ,
Robert Adams  and
Ariane Gallez
David Fortin*
Affiliation:
Departments of Neurosurgery and Neuro-oncology, University of Sherbrooke Hospital, Sherbrooke, Quebec, Canada
Robert Adams
Affiliation:
Department of Neurosurgery, University of Sherbrooke Hospital, Sherbrooke, Quebec, Canada
Ariane Gallez
Affiliation:
Department of Sciences, University of Sherbrooke, Sherbrooke, Quebec, Canada
*
Departments of Neurosurgery and Neuro-oncology, University of Sherbrooke Hospital, Sherbrooke, Quebec, J1H 5N4, Canada.
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.
Objective:

We propose a simple modification to an established blood-brain barrier disruption (BBBD) animal model that allows us to use ketamine/xylazine as the anaesthetic agent, therefore decreasing the complexity and the cost of the model, while maintaining similar efficiency.

Methods:

Sixty-two Long Evans rats were anaesthetized by intraperitoneal injection of ketamine/ xylazine. Osmotic BBBD was performed by administering 25% mannitol into the internal carotid artery in a retrograde fashion from the external carotid. The infusion rate of mannitol, as well as the duration was adjusted in a stepwise fashion to identify optimal parameters for BBBD and minimize complications. As a supplementary step to previously reported models, a vascular clip was applied to the common carotid artery prior to the infusion of mannitol, therefore isolating our model system from the depressant hemodynamic effects of ketamine/xylazine. Evans blue dye was used to control for BBBD intensity.

Results:

Using this model at an initial infusion rate of 0.15 ml/sec, a significant incidence of brain hemorrhage (75%) and a death rate of 62.5% were observed. Decreasing the infusion rate in a stepwise fashion, 0.08 ml/sec was found to produce optimal BBBD, as demonstrated by Evans blue staining. At this rate, 6/7 animals depicted grade II staining, whereas one animal depicted grade IV.

Conclusion:

The application of a clip to the common carotid artery prior to mannitol infusion allowed us to isolate the cerebral circulation from the depressant hemodynamic effects of ketamine/xylazine. This supplementary step produced consistent and efficient BBBD in our animal model.

Type
Experimental Neurosciences
Information
Canadian Journal of Neurological Sciences , Volume 31 , Issue 2 , May 2004 , pp. 248 - 253
Copyright
Copyright © The Canadian Journal of Neurological 2004

References

1.Walker, MD, Alexander, E Jr, Hunt, WE, et al. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. J Neurosurg 1978; 49: 333–343.CrossRefGoogle ScholarPubMed
2.Kroll, RA, Neuwelt, EA. Outwitting the blood-brain barrier for therapeutic purposes: osmotic opening and other means. Neurosurgery 1998; 42: 1083–1099.CrossRefGoogle ScholarPubMed
3.Cosolo, W, Christophidis, N. Blood-brain barrier disruption and methotrexate in the treatment of a readily transplantable intracerebral osteogenic sarcoma of rats. Cancer Res 1987; 47: 6225–6228.Google ScholarPubMed
4.Madajewicz, S, Chowhan, N, Tfayli, A, et al. Therapy for patients with high grade astrocytoma using intraarterial chemotherapy and radiation therapy. Cancer 2000; 88: 2350–2356.3.0.CO;2-R>CrossRefGoogle ScholarPubMed
5.Remen, LG, Trail, PA, Hellstrom, I, Hellstrom, KE, Neuwelt, EA. Enhanced delivery improves the efficacy of a tumor-specific doxorubicin immunoconjugate in a human brain tumor xenograft model. Neurosurgery 2000; 46: 704–709.CrossRefGoogle Scholar
6.Siegal, T, Horowitz, A, Gabizon, A. Doxorubicin encapsulated in sterically stabilized liposomes for the treatment of a brain tumor model: biodistribution and therapeutic efficacy. J Neurosurg 1995; 83: 1029–1037.CrossRefGoogle ScholarPubMed
7.Zlokovic, BV, Apuzzo, MLJ. Strategies to circumvent vascular barriers of the central nervous system. Neurosurgery 1998; 43: 877–878.CrossRefGoogle ScholarPubMed
8.Kroll, RA, Pagel, MA, Muldoon, LL, et al. Improving drug delivery to intracerebral tumor and surrounding brain in a rodent model: a comparison of osmotic versus bradykinin modification of the blood-brain and/or blood-tumor barriers. Neurosurgery 1998; 43: 876–886.CrossRefGoogle ScholarPubMed
9.Grabb, PA, Gilbert, MR. Neoplastic and pharmacological influence on the permeability of an in vitro blood-brain barrier. J Neurosurg 1995; 82: 1053–1058.CrossRefGoogle ScholarPubMed
10.Neuwelt, EA, Maravilla, KR, Frenkel, EP, et al. Use of computerized tomography to evaluate osmotic blood-brain barrier disruption. Neurosurgery 1980; 6: 49–56.CrossRefGoogle ScholarPubMed
11.Neuwelt, EA, Barnett, PA, McCormick, CI, et al. Diffe re ntial permeability of a human brain tumor xenograft in the nude rat: impact of tumor size and method of administration of optimizing delivery of biologically diverse agents. Clin Cancer Res 1998; 4:1549–1555.Google Scholar
12.Oztas, B, Kucuk, M. Intracarotid hypothermic saline infusion: a new method for reversible blood-brain barrier disruption in anaesthetized rats. Neurosci Lett 1995; 190: 203–206.CrossRefGoogle Scholar
13.Robinson, PJ, Rapoport, SI. Model for drug uptake by brain tumors: effects of osmotic treatment and of diffusion in brain. J Cereb Blood Flow Metab 1990; 10: 153–161.CrossRefGoogle ScholarPubMed
14.Rapoport, SI, Hori, M, Klatxo, I. Testing of a hypothesis of osmotic opening of the blood-brain barrier. Am J Physiol 1972; 223: 323–331.CrossRefGoogle ScholarPubMed
15.Neuwelt, EA, Frenkel, EP, Rapoport, S, Barnett, P. Effect of osmotic blood-brain barrier disruption on methotrexate pharmacokinetics in the dog. Neurosurgery 1980; 7: 36–43.CrossRefGoogle ScholarPubMed
16.Cosolo, WC, Martinello, P, Louis, WJ, Christophidis, N. Blood-brain barrier disruption using mannitol: time course and electron microscopy studies. Am J Physiol 1989; 256: R443–R447.Google ScholarPubMed
17.Gummerlock, MK, Neuwelt, EA. The effects of anaesthesia on osmotic blood-brain barrier disruption. Neurosurgery 1990; 26: 268–277.CrossRefGoogle Scholar
18.Remsen, LG, Pagel, MA, McCormack, CI, et al. The influence of anaesthetic choice, PaCO2, and other factors on osmotic blood brain barrier disruption in rats with brain tumor xenografts. Anesth Analg 1999; 88: 559–567.Google ScholarPubMed
19.Fortin, D, McCormick, CI, Remsen, LG, Nixon, R, Neuwelt, EA. Unexpected neurotoxicity of etoposide phosphate administered in combination with other chemotherapeutic agents after blood-brain barrier modification to enhance delivery, using propofol for general anaesthesia, in a rat model. Neurosurgery 2000; 47: 199–207.Google ScholarPubMed