Publications Citing Intracisternal Administration into the CSF

Ref No. Animal Description Volume Dosed (Site) Clodronate Concentration Lipid Composition Lipid Mole % Liposome Type
13 New Zealand White rabbits, 2-2.5 Kg 100µl§ (intracisternal) 5 mg/ml EPC:Chol 84/16 MLV
14 Fisher 344 rats, 2 day 75-100µl (intracranial†) 5 mg/ml EPC:Chol 84/16 MLV


13. F. Trostdorf, W Buck; M. Schmitz-Salue; K. Stuertz, S. J. Hopkins; N. van Rooljen; I. Huitinga; R. Nau.  Reduction of meningeal macrophages does not decrease migration of granulocytes into the CSF and brain parenchyma in experimental pneumococcal meningitis , J. Neurommunol. 99 (1999) 205-210.

Local cell types targeted included meningeal macrophages and choroid plexus macrophages. There was no systematic depletion method and no systematic depletion result.

§Note: The authors cite intracisternal injections with the only specific site mentioned being the cisterna cerebellomedullaris (aka cisterna magna in humans). If this was indeed the injection site for the liposomes, access to the ventricles including the choroidal plexus would be limited, if any, which the authors concede.

The authors further note that meningeal macrophage depletion was limited to 77% state that more complete depletion is likely required for their model, however, they did not confirm that maximal depletion was obtained with their dosing regimen (100 µl q 12 hr X 3 with sacrifice after another 12 hr). This is not a typical regimen for obtaining maximal depletion.

The observation that the rabbits experienced immediate bronchospasms after which death occurred by respiratory failure when >100 µl of clodronate liposomes were injected has not been reported to date in other species and warrant further investigation. An acute anaphylactic-type response to intracisternally dosed liposomes has not been reported in other species. Since the authors prediluted the 100 µl of liposomes with 200 µl of saline, it is possible that some of the clodronate leaked from the liposomes prior to injection as has been reported for this formulation. Additional leakage as the liposomes entered the CSF was also likely as has been reported for clodronate liposomes diluted in serum. Therefore the reaction could have been a result of free clodronate. These control experiments with empty liposomes and free clodronate may have clarified the unexpected result.

14. X. Li; C. Hanson; J. L. Cmarik; S. Ruscetti, Neurodegeneration induced be PVC-211 murine leukemia virus is associated with increased levels of vascular endothelial growth factor and macrophage inflammatory protein 1 alpha and is inhibited be blocking activation of microglia, J. Virol., 83(2009)4912-4922.

Local cell types targeted include microglia. There was no systematic depletion method and no systematic depletion results.

Note†: This paper states that intracranial injections (i.c.) were performed with no other details. The authors do cite Chiavolini, et al, later in the paper (who specifically described a method for intracisternal injection) in reference to unexpected animal deaths. Thus, intracisternal injection may be assumed, but clarification is needed as to the treatment method in order to fully evaluate the results.

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