Preclinical update on regulation of intracranial pressure in relation to idiopathic intracranial hypertension.

BACKGROUND: Elevated intracranial pressure (ICP) is observed in association with a range of brain disorders. One of these challenging disorders is idiopathic intracranial hypertension (IIH), characterized by raised ICP of unknown cause with significant morbidity and limited therapeutic options. In this review, special focus is put on the preclinical research performed in order to understand the pathophysiology behind ICP regulation and IIH. This includes cerebrospinal fluid dynamics, molecular mechanisms underlying disturbances in brain fluids leading to elevated ICP, role of obesity in IIH, development of an IIH model and ICP measurements in rodents. The review also discusses existing and new drug targets for IIH that have been evaluated in vivo. CONCLUSIONS: ICP monitoring in rodents is challenging and different methods have been applied. Some of these methods are invasive, depend on use of anesthesia and only allow short-term monitoring. Long-term ICP recordings are needed to study IIH but existing methods are hampered by several limitations. As obesity is one of the most common risk factors for IIH, a rodent obese model has been developed that mimics some key aspects of IIH. The most commonly used drugs for IIH have been evaluated in vivo for their efficacy at lowering ICP in the existing animal models. These studies suggest these drugs, including acetazolamide, might have limited or no reducing effect on ICP. Two drug targets that can impact ICP in healthy rodents are topiramate and a glucagon-like peptide-1 receptor (GLP-1R) agonist. However, it remains to evaluate their effect in an IIH model with more precise and valid ICP monitoring system. Therefore, continued evaluation in the preclinical research with refined tools is of great importance to further understand the pathophysiology behind disorders with raised ICP and to explore new drug targets.

Topiramate is more effective than acetazolamide at lowering intracranial pressure.

BACKGROUND: The management of idiopathic intracranial hypertension focuses on reducing intracranial pressure to preserve vision and reduce headaches. There is sparse evidence to support the use of some of the drugs commonly used to manage idiopathic intracranial hypertension, therefore we propose to evaluate the efficacy of these drugs at lowering intracranial pressure in healthy rats. METHODS: We measured intracranial pressure in female rats before and after subcutaneous administration of acetazolamide, topiramate, furosemide, amiloride and octreotide at clinical doses (equivalent to a single human dose) and high doses (equivalent to a human daily dose). In addition, we measured intracranial pressure after oral administration of acetazolamide and topiramate. RESULTS: At clinical and high doses, subcutaneous administration of topiramate lowered intracranial pressure by 32% ( p = 0.0009) and 21% ( p = 0.015) respectively. There was no significant reduction in intracranial pressure noted with acetazolamide, furosemide, amiloride or octreotide at any dose. Oral administration of topiramate significantly lowered intracranial pressure by 22% ( p = 0.018), compared to 5% reduction with acetazolamide ( p = >0.999). CONCLUSION: Our in vivo studies demonstrated that both subcutaneous and oral administration of topiramate significantly lowers intracranial pressure. Other drugs tested, including acetazolamide, did not significantly reduce intracranial pressure. Future clinical trials evaluating the efficacy and side effects of topiramate in idiopathic intracranial hypertension patients would be of interest.

A glucagon-like peptide-1 receptor agonist reduces intracranial pressure in a rat model of hydrocephalus.

Current therapies for reducing raised intracranial pressure (ICP) under conditions such as idiopathic intracranial hypertension or hydrocephalus have limited efficacy and tolerability. Thus, there is a pressing need to identify alternative drugs. Glucagon-like peptide-1 receptor (GLP-1R) agonists are used to treat diabetes and promote weight loss but have also been shown to affect fluid homeostasis in the kidney. We investigated whether exendin-4, a GLP-1R agonist, is able to modulate cerebrospinal fluid (CSF) secretion at the choroid plexus and subsequently reduce ICP in rats. We used tissue sections and cell cultures to demonstrate expression of GLP-1R in the choroid plexus and its activation by exendin-4, an effect blocked by the GLP-1R antagonist exendin 9-39. Acute treatment with exendin-4 reduced Na+- and K+-dependent adenosine triphosphatase activity, a key regulator of CSF secretion, in cell cultures. Finally, we demonstrated that administration of exendin-4 to female rats with raised ICP (hydrocephalic) resulted in a GLP-1R-mediated reduction in ICP. These findings suggest that GLP-1R agonists can reduce ICP in rodents. Repurposing existing GLP-1R agonist drugs may be a useful therapeutic strategy for treating raised ICP.

Acetazolamide lowers intracranial pressure and modulates the cerebrospinal fluid secretion pathway in healthy rats.

Acetazolamide is one of the most widely used drugs for lowering intracranial pressure (ICP) and is believed to reduce cerebrospinal fluid (CSF) secretion via its action on the choroid plexus (CP). In the CP the main driving force for CSF secretion is primarily active transport of Na+ ions facilitated by the Na/K ATPase. Transmembrane water channels, known as aquaporins (AQP), are also present in the CP and play an important role in the movement of water. In the present study, we investigated the effect of a single dose acetazolamide on the activity of the Na/K ATPase and ICP. Furthermore, we investigated the expression of Na/K ATPase, AQP1 and AQP4 in the CP tissue following acetazolamide treatment. 12 female Sprague Dawley rats were randomized into two groups; one group received 200mg acetazolamide and the other vehicle treatment. All animals were subjected to ICP recordings and the CP tissue was collected for qPCR and western blot analysis. The effect of acetazolamide on the Na/K ATPase activity was evaluated in an in vitro assay of primary CP epithelial cells isolated from rats. Acetazolamide significantly lowered ICP within 10min of injection compared to the vehicle group (P<0.05), reaching a maximum reduction at 55min 66±4% (P<0.00001). Acetazolamide also significantly decreased the activity of the Na/K ATPase in CP epithelial cells compared to vehicle (P=0.0022). Acetazolamide did not change the AQP1, AQP4 or Na/K ATPase mRNA content in the CP tissue. However, we did record an increase in the amount of AQP1 (p=0.0152) and Na/K ATPase (p=0.0411) protein in the membrane fraction of the CP, but not AQP4 (p=0.0649). A single dose of acetazolamide lowers ICP and modulates the CSF secretion pathway in healthy rats - Firstly, by inhibiting the Na/K ATPase to slow the CSF production, secondly, by increasing AQP1 and Na/K ATPase protein in the membrane of the CP epithelial cells.

Idiopathic intracranial hypertension, hormones, and 11ß-hydroxysteroid dehydrogenases.

Idiopathic intracranial hypertension (IIH) results in raised intracranial pressure (ICP) leading to papilledema, visual dysfunction, and headaches. Obese females of reproductive age are predominantly affected, but the underlying pathological mechanisms behind IIH remain unknown. This review provides an overview of pathogenic factors that could result in IIH with particular focus on hormones and the impact of obesity, including its role in neuroendocrine signaling and driving inflammation. Despite occurring almost exclusively in obese women, there have been a few studies evaluating the mechanisms by which hormones and adipokines exert their effects on ICP regulation in IIH. Research involving 11ß-hydroxysteroid dehydrogenase type 1, a modulator of glucocorticoids, suggests a potential role in IIH. Improved understanding of the complex interplay between adipose signaling factors such as adipokines, steroid hormones, and ICP regulation may be key to the understanding and future management of IIH.

A novel method for long-term monitoring of intracranial pressure in rats.

BACKGROUND: In preclinical neurological studies, monitoring intracranial pressure (ICP) in animal models especially in rodents is challenging. Further, the lack of methods for long-term ICP monitoring has limited the possibilities to conduct prolonged studies on ICP fluctuations in parallel to disease progression or therapeutic interventions. For these reasons we aimed to set up a simple and valid method for long-term ICP recordings in rats. NEW METHOD: A novel ICP method employing epidural probes was developed and validated by simultaneously ICP recordings in the lateral ventricle and in the epidural space. The two pressures were recorded twice a week for 59 days and the correlation was studied. RESULTS: The two pressure recordings correlated exceptionally well and the R(2) values on each recording day ranged between 0.99 and 1.00. However, the ventricular probes caused a number of complications including loss of patency and tissue damage probably due to cerebral infection, whereas the epidural probes were safe and reliable throughout the entire study. COMPARISON WITH EXISTING METHODS: Epidural probes are much easier to implant than ventricular probes. In addition, these new probes are far less invasive and induce no apparent mechanical tissue damage and highly decrease the infection risk associated with ICP recordings. CONCLUSION: Epidural ICP recorded with this new method is identical to the ventricular ICP for at least 59 days but is far less complicated and safer for the animals. The long-term method described is reliable, valid, inexpensive, and may be used in multiple disease models to study ICP.

Influence of sex differences on the progression of cancer-induced bone pain.

BACKGROUND: Pain caused by bone metastases has a severe impact on the quality of life for many patients with cancer. Good translational in vivo models are required to understand the molecular mechanism and develop better treatment. In the current study we evaluated the influence of sex differences on the progression of cancer-induced bone pain. MATERIALS AND METHODS: 4T1-luc2 mammary cancer cells were introduced into the femoral cavity of female and male BALB/cJ mice. Bioluminescence tumor signal, pain-related behavior and bone degradation were monitored for 14 days. RESULTS: Female mice demonstrated a significantly greater bioluminescence signal on day 2 compared to male mice and, in addition, a significant earlier onset of pain-related behavior was observed in the females. No sex difference was observed for bone degradation. Finally, a strong correlation between pain-related behavior and bone degradation was observed for both sexes. CONCLUSION: Although differences were observed between the sexes, these were minor and did not affect the overall progression of the pain state.

The role of purinergic receptors in cancer-induced bone pain.

Cancer-induced bone pain severely compromises the quality of life of many patients suffering from bone metastasis, as current therapies leave some patients with inadequate pain relief. The recent development of specific animal models has increased the understanding of the molecular and cellular mechanisms underlying cancer-induced bone pain including the involvement of ATP and the purinergic receptors in the progression of the pain state. In nociception, ATP acts as an extracellular messenger to transmit sensory information both at the peripheral site of tissue damage and in the spinal cord. Several of the purinergic receptors have been shown to be important for the development and maintenance of neuropathic and inflammatory pain, and studies have demonstrated the importance of both peripheral and central mechanisms. We here provide an overview of the current literature on the role of purinergic receptors in cancer-induced bone pain with emphasis on some of the difficulties related to studying this complex pain state.