Investigators first speculated that intracranial pressure (ICP) may have a role in modulating optic nerve changes associated with glaucoma nearly 90 years ago. More recent retrospective and prospective studies have confirmed an association between reduced ICP and primary open-angle glaucoma (POAG) and normal-tension glaucoma (NTG), suggesting ICP as a risk factor for glaucoma. Unfortunately, the association between ICP and glaucomatous optic neuropathies has been difficult to study in a controlled environment because of the absence of a suitable animal model.
In an article published in PLOS ONE in December 2013, Michael P. Fautsch, Ph.D., at Mayo Clinic's campus in Rochester, Minnesota, and colleagues reported a novel rat model that can be used to study the role of ICP modulation on optic neuropathies. "The rat intraventricular cannula (IVC) model is the first comprehensive animal model in which ICP can be manually reduced or increased over an extended period of time to study the role of ICP in optic nerve pathology," says Dr. Fautsch.
In a study carried out in accordance with recommendations in the "Guide for the Care and Use of Laboratory Animals" of the National Institutes of Health, Dr. Fautsch and his team compared stainless steel cannulae placement in the cisterna magna or lateral ventricle in Sprague-Dawley and brown Norway rats. The cannula was attached to a pressure transducer connected to a computer that recorded real-time ICP. Based on their ability to maintain an implanted cannula for at least four weeks with minimal surgical issues, the brown Norway rat with a stainless steel cannula inserted into the lateral ventricle became the animal of choice for subsequent experiments.
To complete the model, a column filled with artificial cerebrospinal fluid (CSF) was placed so that the top level of the artificial CSF fluid was at head level of the brown Norway rat. The artificial CSF syringe column was attached in parallel with the pressure transducer. ICP at baseline and with column lowered or raised at various positions were compared using the unpaired Student t-test.
- Average ICP at head level was 5.5±1.5 cm water.
- Positioning of the artificial CSF column by 2 or 4 cm below head level reduced ICP by 33 percent and 73 percent when compared with baseline ICP.
- Raising the column above head level by 2 or 4 cm showed a 5 percent and 38 percent increase in ICP.
- Histologic studies confirmed correct cannula placement and indicated minimal invasive damage to brain tissues.
"We believe the ICP is lowered by outward drainage of CSF, possibly due to a siphon effect, when the artificial CSF column is lowered," says Dr. Fautsch. "ICP would be raised by infusion of artificial CSF from the attached column based on a pressure difference, when the column is raised. Based on these data of CSF outflow, rats appear to be a good choice for a model animal, due to similarities in CSF drainage pathways with humans."
The rat IVC model has been shown to measure ICP successfully over sustained periods of time, while the attached artificial CSF column enables the investigator to lower or raise ICP in a controlled fashion. "This model can be an invaluable tool in bridging current knowledge gaps," says Dr. Fautsch. "It offers a viable method to study the effect of intracranial hypertension and hypotension on various ocular as well as systemic pathologies, such as stroke, brain injury and cardiac arrest, where ICP plays an important role."
For more information
Chowdhury RU, et al. A novel rat model to study the role of intracranial pressure modulation on optic neuropathies. PLOS ONE. 2013;8:e82151.