Intracranial Pressure and Its Relationship to Glaucoma: Current Understanding and Future Directions

Retrospective and prospective studies looking at the role of cerebrospinal fluid pressure (CSFP)/intracranial pressure (ICP) have stimulated new theories and hypotheses regarding the underlying causal events for glaucoma. Most recently, studies supporting a low CSFP/ICP as a risk factor for glaucoma have been published. This review summarizes the current understanding of CSFP/ICP and its potential role in the pathogenicity of the disease

Intracranial Pressure and Its Relationship to Glaucoma: Current Understanding and Future Directions

Retrospective and prospective studies looking at the role of cerebrospinal fluid pressure (CSFP)/intracranial pressure (ICP) have stimulated new theories and hypotheses regarding the underlying causal events for glaucoma. Most recently, studies supporting a low CSFP/ICP as a risk factor for glaucoma have been published. This review summarizes the current understanding of CSFP/ICP and its potential role in the pathogenicity of the disease

Consensus Recommendation for Mouse Models of Ocular Hypertension to Study Aqueous Humor Outflow and Its Mechanisms.

Due to their similarities in anatomy, physiology, and pharmacology to humans, mice are a valuable model system to study the generation and mechanisms modulating conventional outflow resistance and thus intraocular pressure. In addition, mouse models are critical for understanding the complex nature of conventional outflow homeostasis and dysfunction that results in ocular hypertension. In this review, we describe a set of minimum acceptable standards for developing, characterizing, and utilizing mouse models of open-angle ocular hypertension. We expect that this set of standard practices will increase scientific rigor when using mouse models and will better enable researchers to replicate and build upon previous findings

A novel rat model to study the role of intracranial pressure modulation on optic neuropathies.

Reduced intracranial pressure is considered a risk factor for glaucomatous optic neuropathies. All current data supporting intracranial pressure as a glaucoma risk factor comes from retrospective and prospective studies. Unfortunately, there are no relevant animal models for investigating this link experimentally. Here we report a novel rat model that can be used to study the role of intracranial pressure modulation on optic neuropathies. Stainless steel cannulae were inserted into the cisterna magna or the lateral ventricle of Sprague-Dawley and Brown Norway rats. The cannula was attached to a pressure transducer connected to a computer that recorded intracranial pressure in real-time. Intracranial pressure was modulated manually by adjusting the height of a column filled with artificial cerebrospinal fluid in relation to the animal's head. After data collection the morphological appearance of the brain tissue was analyzed. Based on ease of surgery and ability to retain the cannula, Brown Norway rats with the cannula implanted in the lateral ventricle were selected for further studies. Baseline intracranial pressure for rats was 5.5 ± 1.5 cm water (n=5). Lowering of the artificial cerebrospinal fluid column by 2 cm and 4 cm below head level reduced ICP to 3.7 ± 1.0 cm water (n=5) and 1.5 ± 0.6 cm water (n=4), a reduction of 33.0% and 72.7% below baseline. Raising the cerebrospinal fluid column by 4 cm increased ICP to 7.5 ± 1.4 cm water (n=2) corresponding to a 38.3% increase in intracranial pressure. Histological studies confirmed correct cannula placement and indicated minimal invasive damage to brain tissues. Our data suggests that the intraventricular cannula model is a unique and viable model that can be used to study the effect of altered intracranial pressure on glaucomatous optic neuropathies

ATP sensitive potassium channel openers: A new class of ocular hypotensive agents

ATP sensitive potassium (K(ATP)) channels connect the metabolic and energetic state of cells due to their sensitivity to ATP and ADP concentrations. K(ATP) channels have been identified in multiple tissues and organs of the body including heart, pancreas, vascular smooth muscles and skeletal muscles. These channels are obligatory hetero-octamers and contain four sulfonylurea (SUR) and four potassium inward rectifier (K(ir)) subunits. Based on the particular type of SUR and K(ir) present, there are several tissue specific subtypes of K(ATP) channels, each with their own unique set of functions. Recently, K(ATP) channels have been reported in human and mouse ocular tissues. In ex vivo and in vivo model systems, K(ATP) channel openers showed significant ocular hypotensive properties with no appearance of toxic side effects. Additionally, when used in conjunction with known intraocular pressure lowering drugs, an additive effect on IOP reduction was observed. These K(ATP) channel openers have also been reported to protect the retinal ganglion cells during ischemic stress and glutamate induced toxicity suggesting a neuroprotective property for this drug class. Medications that are currently used for treating ocular hypertensive diseases like glaucoma do not directly protect the affected retinal cells, are sometimes ineffective and may show significant side effects. In light of this, K(ATP) channel openers with both ocular hypotensive and neuroprotective properties, have the potential to develop into a new class of glaucoma therapeutics

ATP-sensitive potassium (KATP) channel openers diazoxide and nicorandil lower intraocular pressure by activating the Erk1/2 signaling pathway.

Elevated intraocular pressure is the most prevalent and only treatable risk factor for glaucoma, a degenerative disease of the optic nerve. While treatment options to slow disease progression are available, all current therapeutic and surgical treatments have unwanted side effects or limited efficacy, resulting in the need to identify new options. Previous reports from our laboratory have established a novel ocular hypotensive effect of ATP-sensitive potassium channel (KATP) openers including diazoxide (DZ) and nicorandil (NCD). In the current study, we evaluated the role of Erk1/2 signaling pathway in KATP channel opener mediated reduction of intraocular pressure (IOP). Western blot analysis of DZ and NCD treated primary normal trabecular meshwork (NTM) cells, human TM (isolated from perfusion cultures of human anterior segments) and mouse eyes showed increased phosphorylation of Erk1/2 when compared to vehicle treated controls. DZ and NCD mediated pressure reduction (p0.1). Histologic evaluation of transmission electron micrographs from DZ + U0126 and NCD + U0126 treated eyes revealed no observable morphological changes in the ultrastructure of the conventional outflow pathway. Taken together, the results indicate that the Erk1/2 pathway is necessary for IOP reduction by KATP channel openers DZ and NCD

Changes in ICP due to manual manipulation of artificial CSF column.

<p>A) Representative ICP graph annotated with boxes and arrows to mark the points where the artificial CSF column was lowered or raised with reference to the animal’s head level. Lowering or raising of the artificial CSF column caused corresponding decrease or increase of ICP. B) Average ICP of all animals, with the artificial CSF column at various positions. </p

Representative picture showing implanted cannula after surgery.

<p>A) The stainless steel cannula was inserted through the guide cannula (enclosed by the threaded pedestal) and attached to the latter through a locking mechanism. The cannula assembly was secured to the skull with dental cement and 4 stainless steel screws fitted into the skull. The guide cannula had an external 3 mm post to which PE60 tubing was connected. B) Following surgery, a stylet was inserted and screwed onto the threaded pedestal of the guide cannula to prevent introduction of extraneous materials into the brain ventricle.</p