CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 6, Issue 4, 2007

Although less frequent among men, migraine affects almost one third of reproductive women, transforming this disorder into a significant public health problem with enormous socioeconomic impact. The last decade however, has seen a great improvement within both the scientific and the clinical fields: the 1988 international classification of headache disorders followed by the release of sumatriptan into the market opened novel avenues. For the first time, clear diagnostic criteria were established, and for the first time a drug targeting migraine, became available. After sumatriptan several other agonists at 5- HT1B and 5-HT1D receptors have been developed constituting a new antimigraine drug class, the so-called triptans. Limitations in their use, mainly due to vascular contraindications keep the field, searching for new potential targets that modulate pain neurotransmission exclusively within the trigeminovascular system. The recently cloned serotonin receptor subtypes 5-HT1F and the 5-HT7 have been shown to exert little or no vasoactive properties, and therefore are considered potential targets for antimigraine drugs with an improved safety profile. Apart from serotonin, other trigeminal and brainstem neurotransmission systems have been investigated. CGRP literature is probably the largest, following by reports implicating the glutamate receptors. CGRP receptor antagonists showed efficacy not only in animal models of migraine but in clinical trials as well. Adenosine and NO pathways are more recent targets. In addition to brain neurotransmission, modulation of cortical spreading phenomenon may influence migraine headache. Neuroimaging and genetic data shows promising results. Drugs with already proven prophylactic efficacy in migraine after well designed clinical trials analyses have also been found to modulate the cortical spreading depression in laboratory animals, suggesting that inhibition of cortical spreading depression phenomenon is an important pathway to control the migraine frequency and severity. Scientists working within the migraine field report in this issue the most recent achievements in their field. Undoubtedly, cephalic pain and migraine in particular, will be less resistant in the near future and patients suffering from these disorders will have the opportunity to get their lost quality of life back.

Serotonin was the first neurotransmitter believed to be involved in cephalic pain transfer forward to the cortex, but the precise mechanism was confirmed only after sumatriptan, a 5-HT1B/1D high affinity agonist, was introduced in the acute treatment of migraine. Although very efficient for migraine relief, activation of 5-HT1B receptor may also cause vasoconstriction outside brain, within the heart arteries for example. Unlike 5-HT1B, the 5-HT1D receptor is not located in vascular tissues but exclusively within neuronal, but high affinity agonists for 5-HT1D failed to prove clinical significance in randomized trials. The recent clone of 5-HT1F receptor together with data showing that sumatriptan exerts high affinity for this receptor subtype generated high expectations. Potent agonists for 5-HT1F receptors were effective in animal models for migraine and later clinical trials showed efficacy even in humans, introducing the first line future anti-migraine drugs. Apart from 5-HT1F, another new cloned 5-HT subtype receptor, the 5-HT7 also attracts attention. Recently developed and clinically tested selective 5HT7 antagonists SB-269970-A and SB-656104-A suggest that the receptor may play a role in other CNS disorders including anxiety and cognitive disturbances, suggesting a potential role for the migraine prophylaxis. These data and speculations are discussed in details in this paper with special references.

The pathophysiology of tension-type headache is still far from clear, although recent advances in basic and clinical research have increased our knowledge about mechanisms underlying this disorder. Experimental studies suggest that increased excitability of the CNS generated by repetitive and sustained pericranial myofascial input may be responsible for transformation of episodic tension-type headache into chronic form. Future studies should focus on the identification of the source of peripheral nociception in patients with tension-type headache and the development of more effective and specific treatment modalities.

Primary headaches are among the most prevalent neurological disorders, afflicting up to 16% of the adult population. Associated pain originates from intracranial blood vessels that are innervated by sensory nerves storing several neurotransmitters. In primary headaches, there is a clear association between the headache and the release of calcitonin gene-related peptide (CGRP) but not with other neuronal messengers. The specific purpose of this review is to describe CGRP in the human cranial circulation and to elucidate a possible role for a specific antagonist in the treatment of primary headaches. Acute treatment by administration of a triptan (5-HT1B/1D agonist) results in alleviation of the headache and normalization of the elevated CGRP level. The mechanism of action of triptans involves vasoconstriction of intracranial vessels and a presynaptic inhibitory effect of the trigeminal sensory nerves. The central role of CGRP in migraine and cluster headache pathophysiology has led to the search for small molecule CGRP antagonists, which would predictably have less cardiovascular side effects as compared to the triptans. The initial pharmacological profile of such a group of compounds has recently been disclosed. These compounds have high selectivity for human CGRP receptors and are reported to be efficacious in the relief of acute attacks of migraine.

Within the last decades significant progress has been made in the understanding of the underlying pathophysiological mechanisms of migraine. There is a general agreement now that migraine is not only a vascular phenomenon but also a genetically determined heterogenic ion-channelopathy resulting in cortical-spreading-depression-like events, the temporary impairment of antinociceptive structures of the brainstem and the activation of the trigeminal-vascular system. The development and use of drugs targeting ion-channels and subsequently reducing cortical excitability appears as a promising avenue for both the acute treatment of migraine and migraine prevention. This review summarizes the current knowledge and evidence for GABAergic drugs in the treatment of migraine.

Glutamate (Glu) is the principal excitatory neurotransmitter in the central nervous system. Its receptors are classified into ionotropic receptors, which are ion channels and include NMDA, AMPA and kainate receptors, named after the agonists that selectively bind to them, and metabotropic receptors, which are G-protein coupled receptors. The trigeminal system is considered to play a key role in migraine pathophysiology, trafficking pain signals from the head and face to the trigeminal nucleus caudalis. The role of glutamate in the pathophysiology of migraine is implicated by data from animal and human studies. Animal studies include experiments of cortical spreading depression, studies of c-fos protein expression in trigeminal nucleus caudalis, studies of plasma protein extravasation and electrophysiological studies. Human studies investigating the role of Glu in migraine pathogenesis measured the levels of Glu in plasma, platelets and cerebrospinal fluid, studied its effect on migraine symptoms and examined the effect of Glu in modulating sensitization. Findings from both the animal and the human studies suggest a link between glutamate and migraine and further suggest that glutamate plays a key role in migraine mechanisms. In the future, efforts should be made to further investigate the role of glutamate in migraine pathogenesis and, subsequently, in migraine treatment.

The potent vasodilatator and messenger molecule nitric oxide (NO) is believed to play a key role in migraine pathogenesis. NO donors such as glyceryl trinitrate (GTN) can cause headache. Infusion of GTN leads to a migraine attack in migraineurs with a latency of 4 to 6 hours. In this review we focus in the role of nitric oxide and the transcription factor nuclear factor-κB (NF-κB) in migraine pathophysiology in humans and animal models. NO is involved in pain transmission, hyperalgesia, chronic pain, inflammation and central sensitization mostly in a cyclic guanosinemonophosphate (cGMP) dependent way. We aim to illustrate how NO is implicated in the induction of a migraine attack in migraineurs and how experimental animal models may help to elucidate the mechanisms of the human GTN response. Because of the role of NO in migraine we try to assess if and how the action of preventative migraine drugs involves the NO pathways. More knowledge about the involvement of NO in the genesis of migraine headache may also provide possible future therapeutic targets for acute migraine therapy.

Since the discovery of the first antipsychotic drug, chlorpromazine, in the early 1950s, all effective antipsychotic drugs have been found to share the common property of dopamine D2 receptor antagonism. There has been some suggestion that simple D2 receptor antagonism may not confer optimal antipsychotic efficacy. Currently available antipsychotic drugs leave many symptoms of the illness untreated and cause unacceptable side effects. Recent research in schizophrenia suggests a number of potential new non-D2 targets for pharmacotherapy including glutamate, acetylcholine and serotonin neurotransmitter systems. This review summarises the main neurochemical theories of schizophrenia, and, in the light of these, examines possible therapeutic targets for new antipsychotic drugs.

Parkinson’s disease (PD) is a common and debilitating degenerative disease resulting from massive degenerative loss of dopamine neurons, particularly in the substantia nigra. The most classic therapy for PD is levodopa administration, but the efficacy of levodopa treatment declines as the disease progresses. The neuroprotective strategies to rescue nigral dopamine neurons from progressive death are currently being explored, and among them, the Chinese herbs and herbal extracts have shown potential clinical benefit in attenuating the progression of PD in human beings. Growing studies have indicated that a range of Chinese herbs or herbal extracts such as green tea polyphenols or catechins, panax ginseng and ginsenoside, ginkgo biloba and EGb 761, polygonum, triptolide from tripterygium wilfordii hook, polysaccharides from the flowers of nerium indicum, oil from ganoderma lucidum spores, huperzine and stepholidine are able to attenuate degeneration of dopamine neurons and sympotoms caused by the neurotoxins 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) in vitro and in vivo conditions. In addition, accumulating data have suggested that Chinese herbs or herbal extracts may promote neuronal survival and neurite growth, and facilitate functional recovery of brain injures by invoking distinct mechanisms that are related to their neuroprotective roles as the antioxidants, dopamine transporter inhibitor, monoamine oxidase inhibitor, free radical scavengers, chelators of harmful metal ions, modulating cell survival genes and signaling, anti-apoptosis activity, and even improving brain blood circulation. New pharmaceutical strategies against PD will hopefully be discovered by understanding the various active entities and valuable combinations that contribute to the biological effects of Chinese herbs and herbal extracts.

3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, generically termed statins, are widely prescribed for their cholesterol-lowering properties. In addition to lipid-lowering properties, statins have pleiotropic effects including anti-inflammatory, anti-apoptotic, and antiproliferative effects. Recently, data from experimental and observational studies have indicated that statins could also become a treatment option for diseases of the central nervous system (CNS). Many neurodegenerative diseases particularly affect the retina and other ocular structures and are the cause for blindness. This review, focused on recent clinical and experimental data, discusses known and putative mechanisms of statin actions underlying neuroprotective effects in relevant retinal and eye diseases. In addition, it presents evidence for the role of heat shock proteins (Hsps) as target of statin-mediated neuroprotective effects in ocular diseases.

Epilepsy is a neurological disorder in which normal brain function is disrupted as a consequence of intensive and synchronous burst activity from neuron assemblies. Epilepsies result from long-lasting plastic changes in the brain affecting neurotransmitter release, the properties of receptors and channels, synaptic reorganization and astrocyte activity. There is considerable evidence for alterations in glutamatergic and GABAergic synaptic transmission in the origin of the paroxysmal depolarization shifts that initiate epileptic activity. However, recent studies on non-synaptic transmission, receptor mobility and glia-neuron signaling pathways suggest that extrasynaptic GABA and glutamate receptors may play an important role in seizure initiation, maintenance and arrest. Extracellular aminoacids such as glutamate, aspartate, glycine and GABA seem to communicate neurons and glial cells acting primarily on extrasynaptic receptors. Synaptic and extrasynaptic glutamate and GABA receptors have been show to play different roles in neuronal excitability. NMDA and GABAA receptors expressed in a single neuron can be differentially regulated based on subcellular localization, and it has been proposed that distinct regulation of synaptic versus extrasynaptic receptors provides a mechanism for receptor adaptation in response to a variety of stimuli. Furthermore, glutamate and GABA receptors are highly mobile, and the number and composition of extrasynaptic receptors can be modulated by several factors. This review addresses recent advances in our understanding of the role of extrasynaptic receptors in epilepsy, suggesting that extrasynaptic receptors and their mechanisms of regulation are expected to be important pharmacological targets.