Potential biological targets for bioassay development in drug discovery of Sturge–Weber syndrome

Abstract

Sturge-Weber Syndrome (SWS) is a neurocutaneous disease with clinical manifestations including ocular (glaucoma), cutaneous (port-wine birthmark), neurologic (seizures), and vascular problems. Molecular mechanisms of SWS pathogenesis are initiated by the somatic mutation in GNAQ. Therefore, no definite treatments exist for SWS and treatment options only mitigate the intensity of its clinical manifestations. Biological assay design for drug discovery against this syndrome demands comprehensive knowledge on mechanisms which are involved in its pathogenesis. By analysis of the interrelated molecular targets of SWS, some in vitro bioassay systems can be allotted for drug screening against its progression. Development of such platforms of bioassay can bring along the implementation of high-throughput screening of natural or synthetic compounds in drug discovery programs. Regarding the fact that study of molecular targets and their integration in biological assay design can facilitate the process of effective drug discovery; some potential biological targets and their respective biological assay for SWS drug discovery are propounded in this review. For this purpose, some biological targets for SWS drug discovery such as acetylcholinesterase, alkaline phosphatase, GABAergic receptors, Hypoxia-Inducible Factor (HIF)-1α and 2α are suggested.

Atlas of Nervous System Vascular Malformations: A Systematic Review

“…There are other treatment approaches, such as modulation through bioactive compounds, that induce fibronectin expression or carbonic anhydrase enzyme and acetylcholinesterase, which focus on decreasing the severity of glaucoma. This approach includes sirolimus, which inhibits the mTOR pathway that is characteristically hyperactivated in SWS and other vascular alterations [ 70 ].…”

“…Although clinical data may be useful in this process, such data are not entirely decisive, given that at a clinical level there may be silent courses, as in the cases of CCT [ 58 ] and small CAs [ 31 ] or clinical manifestations that are closely similar, such headaches and seizures that are present in most of the different vascular malformation cases [ 17 , 20 , 32 , 33 , 49 , 50 , 51 , 60 , 62 , 68 ]. An example of a fairly useful clinical feature is port wine stain in the case of SWS [ 63 , 64 , 65 ]; however, this syndrome will only occur in 8% to 33% of the subjects with the skin mark [ 70 ]. In addition, SWS may be present without the presence of port wine stain.…”

“…Despite the emerging options for drug treatment for vascular malformations, sclerotherapy, embolization, and surgical resection or laser cytoreduction interventions continue to be the most optimal approach options in most cases, as they allow for the handling of large, surgically accessible lesions; in difficult cases, endovascular sclerotherapy and embolization allow for the treatment of such difficult-to-reach lesions [ 9 , 19 , 70 , 80 ]. The exception is CCT or asymptomatic AVMs in older adults, which can generally be managed with a conservative surveillance approach [ 58 , 59 , 80 ].…”

“…Relevant examples of such progress include the atorvastatin proposal as a ROCK inhibitor (which leadsg to a decreased incidence of lesions and hemorrhages in CAs [ 74 ]), propranolol (which is suggested as an EndMT inhibitor by modulating the TGF pathway and transforming growth factor -β in CA [ 41 , 75 , 76 ]), or pioglitazone, silibinin, norcantharidine, berberine, protocatechuic aldehyde, hemodine, tuberin, simvastatin, and sirolimus (as regulators of fibronectin expression in SWS [ 70 , 73 ]). In particular, sirolimus has been proposed as a treatment alternative for complicated vascular malformations [ 9 ].…”

Genetic syndromes with vascular malformations – update on molecular background and diagnostics

“…The α subunit of G protein (a GNAQ expression product) is then released and activates enzymes and effector proteins involved in signaling pathways necessary for vascular development. Alterations of GNAQ are indicated in SWS pathogenesis [159,164,165] exclusively in tissue with capillary malformation [167,168]. On the other hand, Sundaram et al suggested that the variation p.Arg183Gln, which is the most common alteration in SWS, is not only linked with vascular malformations, but may also affect brain parenchyma, which could explain the brain pathology present in SWS [169,170].…”