Use of calcium channel blockers for glaucoma.

Calcium channel blockers (CCBs), which alter the intracellular calcium concentration by modifying calcium flux across cell membranes and affect various intracellular signaling processes, have been long and widely used to treat essential hypertension and certain types of cardiac diseases such as angina pectoris. Among five subtypes of calcium channels, only specific agents for L-type calcium channels have been used as therapeutics. Animal experiments have indicated that topical application of CCBs, especially verapamil, caused significant intraocular pressure (IOP) reductions, while ocular hypotensive effects in humans were not substantial. Although the results obtained for nifedipine and nimodipine were not always consistent, CCBs generally dilate isolated ocular vessels and increase ocular blood flow in experimental animals, normal humans, and patients with open-angle glaucoma (OAG). Several single-centered, hospital-based, prospective studies have suggested that nimodipine, brovincamine, and nilvadipine had beneficial effects on visual function not only in normal humans but also in patients with OAG, while the results of population-based and case-controlled studies were not always consistent with those obtained in hospital-based studies. In vitro studies showed that CCBs exerted neuroprotective effects on neurons undergoing apoptosis and necrosis. Although the neuroprotective effects of CCBs have been well documented in experimental cerebral ischemia models, no controlled studies have shown the clinical efficacy of CCBs in stroke or cerebral ischemia. Neuroprotective effects also were documented in retinal ganglion cells and photoreceptors in experimental animals. Some ophthalmic beta-adrenoceptor antagonists, especially betaxolol, interact with L-type calcium channels and show calcium channel-blocking activity, which may be partly responsible for the neuroprotective effects of these drugs reported in experimental animals. Based on the reported findings of CCBs and that the results of clinical studies in acute cerebral ischemia may not be directly applicable to a chronic neurodegenerative ocular disorder, such as OAG, CCBs deserve future study to investigate strategies that are additive or synergetic to ocular hypotensive therapy for OAG, especially in patients with lower IOP.

Wormwood (Artemisia absinthium L.)--a curious plant with both neurotoxic and neuroprotective properties?

The medical use of the wormwood plant Artemisia absinthium L. dates back to at least Roman times, while during the last century this tradition was seemingly on the decline due to fears of absinthism, a syndrome allegedly caused by the wormwood-flavoured spirit absinthe and more specifically as a result of thujone, a monoterpene ketone often present in the essential oil of wormwood. If threshold concentrations are exceeded, thujone does in fact exhibit neurotoxic properties leading to dose-dependent tonic-clonic seizures in animals, likely caused by GABA type A receptor modulation. Research has shown that the concentrations of thujone present in absinthe were not sufficient to exceed these thresholds, and the marketing of wormwood-flavoured alcoholic beverages has ultimately been reinstated. The declining fears of absinthism may have led to a revival of the medical uses of wormwood, evidenced by several experimental reports, e.g. on the treatment of Crohn's disease. Most recently in this journal, neuroprotective properties of wormwood were detected in rats, and the plant was suggested to be possibly beneficial in the treatment of strokes. While these results sound promising and worthwhile for further investigation, the well-defined profile of adverse properties of wormwood demands a more cautious interpretation of these results. It remained unclear in the studies, for example, if the threshold dose for thujone (e.g. as set by the European Medicines Agency) would be exceeded during therapeutic usage. Due to the colourful history of wormwood, its application in humans should be preceded by a thorough and careful risk-benefit analysis.

New approaches to neuroprotection in infant heart surgery.

Advances in surgical techniques and perioperative management have led to dramatic improvements in outcomes for children with complex congenital heart disease (CHD). As the number of survivors continues to grow, clinicians are becoming increasingly aware that adverse neurodevelopmental outcomes after surgical repair of CHD represent a significant cause of morbidity, with widespread neuropsychologic deficits in as many as 50% of these children by the time they reach school age. Modifications of intraoperative management have yet to measurably impact long-term neurologic outcomes. However, exciting advances in our understanding of the underlying mechanisms of cellular injury and of the events that mediate endogenous cellular protection have provided a variety of new potential targets for the assessment, prevention, and treatment of neurologic injury in patients with CHD. In this review, we will discuss the unique challenges to developing neuroprotective strategies in children with CHD and consider how multisystem approaches to neuroprotection, such as ischemic preconditioning, will be the focus of ongoing efforts to develop new diagnostic tools and therapies. Although significant challenges remain, tremendous opportunity exists for the development of diagnostic and therapeutic interventions that can serve to limit neurologic injury and ultimately improve outcomes for infants and children with CHD.

Monoamine oxidase: isoforms and inhibitors in Parkinson's disease and depressive illness.

A few years after the foundation of the British Pharmacological Society, monoamine oxidase (MAO) was recognized as an enzyme of crucial interest to pharmacologists because it catalyzed the major inactivation pathway for the catecholamine neurotransmitters, noradrenaline, adrenaline and dopamine (and, later, 5-hydroxytryptamine, as well). Within the next decade, the therapeutic value of inhibitors of MAO in the treatment of depressive illness was established. Although this first clinical use exposed serious side effects, pharmacological interest in, and investigation of, MAO continued, resulting in the characterization of two isoforms, MAO-A and -B, and isoform-selective inhibitors. Selective inhibitors of MAO-B have found a therapeutic role in the treatment of Parkinson's disease and further developments have provided reversible inhibitors of MAO-A, which offer antidepressant activity without the serious side effects of the earlier inhibitors. Clinical observation and subsequent pharmacological analysis have also generated the concept of neuroprotection, reflecting the possibility of slowing, halting and maybe reversing, neurodegeneration in Parkinson's or Alzheimer's diseases. Increased levels of oxidative stress in the brain may be critical for the initiation and progress of neurodegeneration and selective inhibition of brain MAO could contribute importantly to lowering such stress. There are complex interactions between free iron levels in brain and MAO, which may have practical outcomes for depressive disorders. These aspects of MAO and its inhibition and some indication of how this important area of pharmacology and therapeutics might develop in the future are summarized in this review.