Discovery of novel inhibitors for the treatment of glaucoma

We have previously examined the specificities of 28 commercially available compounds, reported to be relatively selective inhibitors of particular serine/threonine-specific protein kinases [Davies, Reddy, Caivano and Cohen (2000) Biochem. J. 351, 95-105]. In the present study, we have extended this analysis to a further 14 compounds. Of these, indirubin-3'-monoxime, SP 600125, KT 5823 and ML-9 were found to inhibit a number of protein kinases and conclusions drawn from their use in cell-based assays are likely to be erroneous. Kenpaullone, Alsterpaullone, Purvalanol, Roscovitine, pyrazolopyrimidine 1 (PP1), PP2 and ML-7 were more specific, but still inhibited two or more protein kinases with similar potency. Our results suggest that the combined use of Roscovitine and Kenpaullone may be useful for identifying substrates and physiological roles of cyclin-dependent protein kinases, whereas the combined use of Kenpaullone and LiCl may be useful for identifying substrates and physiological roles of glycogen synthase kinase 3. The combined use of SU 6656 and either PP1 or PP2 may be useful for identifying substrates of Src family members. Epigallocatechin 3-gallate, one of the main polyphenolic constituents of tea, inhibited two of the 28 protein kinases in the panel, dual-specificity, tyrosine-phosphorylated and regulated kinase 1A (DYRK1A; IC(50)=0.33 microM) and p38-regulated/activated kinase (PRAK; IC(50)=1.0 microM).

In this review, we distinguish among risk factors associated with the development of open-angle glaucoma in individuals with healthy eyes, predictive determinants for the development of open-angle glaucoma in subjects with ocular hypertension, and prognostic factors for the progression of open-angle glaucoma in individuals who already have the disease. We primarily reviewed recent longitudinal population-based epidemiological studies, prospectively planned clinical trials, and cohort studies. Risk factors consistently associated with the development of open-angle glaucoma in individuals with healthy eyes include older age and an approximately 1 mm Hg increase in intraocular pressure (IOP) at baseline. Family history for open-angle glaucoma may be associated with the development of open-angle glaucoma as well. Predictive factors for the development of open-angle glaucoma in individuals with ocular hypertension may be older age, thinner central corneal thickness, higher cup-to-disk ratios of the optic disc, and higher pattern standard deviation values on the Humphrey automated perimeter at baseline. Given multi-center trials that showed similar predictive factors for the development of open-angle glaucoma in individuals with ocular hypertension, a calculator is available to clinicians for assessing the 5-year likelihood of developing open-angle glaucoma in ocular hypertensive patients with certain characteristics. Prognostic factors for the progression of open-angle glaucoma in individuals who already have the condition include older age at baseline, higher IOP at baseline, and thinner central conreal thickness. Self-report of diabetes may be associated with open-angle glaucoma progression. In conclusion, the only modifiable factor associated with open-angle glaucoma that has been consistently identified is elevated baseline IOP. Future research needs to evaluate the importance of others modifiable factors such as IOP fluctuation or nutritional factors.

Rho kinases (ROCKs), the first Rho effectors to be described, are serine/threonine kinases that are important in fundamental processes of cell migration, cell proliferation and cell survival. Abnormal activation of the Rho/ROCK pathway has been observed in various disorders of the central nervous system. Injury to the adult vertebrate brain and spinal cord activates ROCKs, thereby inhibiting neurite growth and sprouting. Inhibition of ROCKs results in accelerated regeneration and enhanced functional recovery after spinal-cord injury in mammals, and inhibition of the Rho/ROCK pathway has also proved to be efficacious in animal models of stroke, inflammatory and demyelinating diseases, Alzheimer's disease and neuropathic pain. ROCK inhibitors therefore have potential for preventing neurodegeneration and stimulating neuroregeneration in various neurological disorders.