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B. C. Samuels, S. J. McKinnon, R. R. Allingham; Lowering Intracranial Pressure: Developing a Model for Normal Tension Glaucoma. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2139.
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Recent studies have shown a link between decreased intracranial pressure (ICP) and open angle glaucoma, yet no animal models exist to examine this relationship. In glaucoma, changes in the pressure gradient between intraocular pressure (IOP) and ICP are hypothesized to create stress and strain in the lamina cribrosa causing retinal ganglion cell loss. We sought to develop a novel technique for manipulating ICP to create a new animal model of glaucoma. The development of this model is necessary to examine the role of the trans-laminar pressure gradient in the pathogenesis of glaucoma.
We modified the techniques of Kusaka and colleagues to implant a small polyethylene (PE-10) tube into the lumbar spinal column of Brown-Norway rats (250-300g) for continuous monitoring of ICP (Kusaka et. al., 2004). The L4-L6 vertebrae were exposed, and a PE-10 tube was inserted into the cerebrospinal fluid space below the dura mater at the level of the cauda equina. The tubing was then attached to a high sensitivity pressure transducer connected to a Powerlab data acquisition unit allowing indirect measurement of the ICP via a lumbar approach. The animal was then placed in a stereotaxic frame and both lateral ventricles were cannulated using glass micropipettes attached to two 25uL Hamilton syringes and a syringe pump. 25ul of mitomycin-C (MMC; 0.4mg/mL) was simultaneously injected into each lateral ventricle and changes in lumbar intracranial pressure recorded.
We were able to consistently measure baseline ICP and small increases in ICP after microinjection of 25uL MMC into the lateral ventricles. Pressure measurement was also sensitive enough to capture small respiration-induced variations in ICP. A representative experiment showed a stable baseline ICP of 6.4mmHg. After microinjection of MMC, the ICP increased to 8.3mmHg at 7.5 minutes post-injection and returned to baseline within 30 minutes.
In a series of acute experiments in anesthetized animals, ICP was monitored while microinjecting MMC into the cerebral ventricles. We confirmed that physiologically relevant changes in intraventricular pressure can be recorded through a lumbar approach. These studies represent the first major technical steps to develop a novel animal model of normal tension glaucoma by chronic reduction of ICP. Our next step is to monitor ICP of conscious animals after treatment with MMC to analyze for chronic reduction of ICP and its effects on retinal ganglion cells and the optic nerve. Once established, this model will permit researchers to investigate the role of ICP and the trans-laminar pressure gradient in the development of glaucoma.
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