Zsófia Majláth

Migraine and neuropeptides

Migraine is a common disabling neurovascular primary headache disorder. The pathomechanism is not clear, but extensive preclinical and clinical studies are ongoing. The structural basis of the leading hypothesis is the trigeminovascular system, which includes the trigeminal ganglion, the meningeal vasculature, and the distinct nuclei of the brainstem, the thalamus and the somatosensory cortex. This review covers the effects of sensory (calcitonin gene-related peptide, pituitary adenylate cyclase-activating polypeptide and substance P), sympathetic (neuropeptide Y) and parasympathetic (vasoactive intestinal peptide) migraine-related neuropeptides and the functions of somatostatin, nociceptin and the orexins in the trigeminovascular system. These neuropeptides may take part in neurogenic inflammation (plasma protein extravasation and vasodilatation) of the intracranial vasculature and peripheral and central sensitization of the trigeminal system. The results of human clinical studies are discussed with regard to the alterations in these neuropeptides in the plasma, saliva and cerebrospinal fluid during or between migraine attacks, and the therapeutic possibilities involving migraine-related neuropeptides in the acute and prophylactic treatment of migraine headache are surveyed.

Drug safety and tolerability in prophylactic migraine treatment

Introduction: Migraine is a frequent, disabling primary headache disorder, whose pathomechanism is not yet fully understood. Prophylactic treatment is advisable for migraineurs with severe or highly frequent attacks, which impair the quality of life. Areas covered: The different types of prophylactic migraine drugs are discussed, with particular regard to potential adverse effects and safety issues. β-Adrenergic blockers, antiepileptic drugs and calcium-channel blockers are drugs widely used for migraine prevention, whereas complementary medicine and onabotulinumtoxin A can be used in selected cases. Expert opinion: The background of the recurrence and chronification of migraine attacks has not been fully clarified, and causative preventive therapy is therefore not currently available. The tolerability and adverse effects of the currently used medications often limit their use. β-Adrenergic receptor blockers may induce adverse cardiovascular events, whereas flunarizine is frequently associated with a weight gain and depression. As most migraine sufferers are young women of child-bearing age, the use of valproate is limited. Topiramate is associated with central nervous system-related side effects. There is a need for future development of pathomechanism-based preventive drugs, and personalized therapy tailored to the patient.

Kynurenines and other novel therapeutic strategies in the treatment of dementia

Dementia is a common neuropsychological disorder with an increasing incidence. The most prevalent type of dementia is Alzheimer’s disease. The underlying pathophysiological features of the cognitive decline are neurodegenerative processes, a cerebrovascular dysfunction and immunological alterations. The therapeutic approaches are still limited, although intensive research is being conducted with the aim of finding neuroprotective strategies. The widely accepted cholinesterase inhibitors and glutamate antagonists did not meet expectations of preventing disease progression, and research is therefore currently focusing on novel targets. Nonsteroidal anti-inflammatory drugs, secretase inhibitors and statins are promising drug candidates for the prevention and management of different forms of dementia. The kynurenine pathway has been associated with various neurodegenerative disorders and cerebrovascular diseases. This pathway is also closely related to neuroinflammatory processes and it has been implicated in the pathomechanisms of certain kinds of dementia. Targeting the kynurenine system may be of therapeutic value in the future.

Brain Aging and Disorders of the Central Nervous System: Kynurenines and Drug Metabolism

INTRODUCTION The kynurenine pathway includes several neuroactive compounds, including kynurenic acid, picolinic acid, 3-hydroxykynurenine and quinolinic acid. The enzymatic cascade of the kynurenine pathway is tightly connected with the immune system, and may provide a link between the immune system and neurotransmission. Main Areas Covered: Alterations in this cascade are associated with neurodegenerative, neurocognitive, autoimmune and psychiatric disorders, such as Parkinsons disease, Huntingtons disease, Alzheimers disease, multiple sclerosis, amyotrophic lateral sclerosis, migraine or schizophrenia. HIGHLIGHTS This review highlights the alterations in this metabolic pathway in the physiological aging process and in different disorders. A survey is also presented of therapeutic possibilities of influencing this metabolic route, which can be achieved through the use of synthetic kynurenic acid analogues, enzyme inhibitors or even nanotechnology.

Kynurenines and Multiple Sclerosis: The Dialogue between the Immune System and the Central Nervous System

Multiple sclerosis is an inflammatory disease of the central nervous system, in which axonal transection takes place in parallel with acute inflammation to various, individual extents. The importance of the kynurenine pathway in the physiological functions and pathological processes of the nervous system has been extensively investigated, but it has additionally been implicated as having a regulatory function in the immune system. Alterations in the kynurenine pathway have been described in both preclinical and clinical investigations of multiple sclerosis. These observations led to the identification of potential therapeutic targets in multiple sclerosis, such as synthetic tryptophan analogs, endogenous tryptophan metabolites (e.g., cinnabarinic acid), structural analogs (laquinimod, teriflunomid, leflunomid and tranilast), indoleamine-2,3-dioxygenase inhibitors (1MT and berberine) and kynurenine-3-monooxygenase inhibitors (nicotinylalanine and Ro 61-8048). The kynurenine pathway is a promising novel target via which to influence the immune system and to achieve neuroprotection, and further research is therefore needed with the aim of developing novel drugs for the treatment of multiple sclerosis and other autoimmune diseases.

Drug safety in acute migraine treatment

Introduction: A number of drugs are available for acute migraine treatment, but they are not all effective for all patients and all attacks. The safety profiles of migraine drugs limit their use in patients with certain comorbid conditions, and adverse effects may also reduce the level of patient compliance. Areas covered: The different types of acute migraine drugs are discussed, with particular regard to safety issues and potential adverse effects. The frequent use of analgesics, ergot alkaloids and triptans may result in the development of medication overuse headache (MOH). Expert opinion: The initiation of a migraine attack is not fully understood, and therefore treatment aimed at causative factors is currently not available. The tolerability and adverse effects of the drugs available at present often limit their use. NSAIDs are frequently associated with gastrointestinal, and possibly also cardiovascular side effects. Ergot alkaloids may induce arterial vasoconstriction, while the administration of triptans is contraindicated in cardiovascular, cerebrovascular and peripheral vascular diseases. The frequent use of these drugs poses the risk of the development of MOH. There is a need for pathomechanism-based drugs, and for the future achievement of personalized medicine.

Drug Targets of Migraine and Neuropathy: Treatment of Hyperexcitability

Migraine and neuropathic pain are common causes of chronic pain. The exact pathomechanism has not been fully clarified for either disorder, but their pathophysiological backgrounds involve several similar mechanisms. Peripheral sensitization occurs in the neuronal elements of the dorsal root ganglion or the trigeminal ganglion, while central sensitization appears in the second-order neurons in the dorsal horn of the spinal cord or the trigeminal nucleus caudalis. Central neuronal hyperexcitability has been implicated in both disorders, and the emerging evidence suggests alterations in the glutamatergic neurotransmission and N-methyl-D-aspartate-receptor activation. Migraine and neuropathic pain additionally share certain clinical features, such as enhanced sensitivity to sensory stimuli and cutaneous allodynia. The pharmacotherapy of both diseases is often challenging, but several antiepileptic drugs that target hyperexcitability are beneficial for both migraine and neuropathic pain. Kynurenine pathway metabolites are capable of influencing the glutamate receptors, and might therefore be novel candidates for future drug development.

Memantine and kynurenic acid: Current neuropharmacological aspects

Glutamatergic neurotransmission, of special importance in the human brain, is implicated in key brain functions such as synaptic plasticity and memory. The excessive activation of N-methyl- D-aspartate (NMDA) receptors may result in excitotoxic neuronal damage; this process has been implicated in the pathomechanism of different neurodegenerative disorders, such as Alzheimer’s disease (AD). Memantine is an uncompetitive antagonist of NMDA receptors with a favorable pharmacokinetic profile, and is therefore clinically well tolerated. Memantine is approved for the treatment of AD, but may additionally be beneficial for other dementia forms and pain conditions. Kynurenic acid (KYNA) is an endogenous antagonist of NMDA receptors which has been demonstrated under experimental conditions to be neuroprotective. The development of a well-tolerated NMDA antagonist may offer a novel therapeutic option for the treatment of neurodegenerative disease and pain syndromes. KYNA may be a valuable candidate for future drug development.

The potential role of kynurenines in Alzheimer’s disease: pathomechanism and therapeutic possibilities by influencing the glutamate receptors

Abstract The pathomechanism of neurodegenerative disorders still poses a challenge to neuroscientists, and continuous research is under way with the aim of attaining an understanding of the exact background of these devastating diseases. The pathomechanism of Alzheimer’s disease (AD) is associated with characteristic neuropathological features such as extracellular amyloid-β and intracellular tau deposition. Glutamate excitotoxicity and neuroinflammation are also factors that are known to contribute to the neurodegenerative process, but a cerebrovascular dysfunction has recently also been implicated in AD. Current therapeutic tools offer moderate symptomatic treatment, but fail to reduce disease progression. The kynurenine pathway (KP) has been implicated in the development of neurodegenerative processes, and alterations in the KP have been demonstrated in both acute and chronic neurological disorders. Kynurenines have been suggested to be involved in the regulation of neurotransmission and in immunological processes. Targeting the KP, therefore, offers a valuable strategic option for the attenuation of glutamatergic excitotoxicity, and for neuroprotection.

Novel Kynurenic Acid Analogues in the Treatment of Migraine and Neurodegenerative Disorders: Preclinical Studies and Pharmaceutical Design

Though migraine and neurodegenerative disorders have a high socioeconomic impact, their therapeutic management has not been fully addressed. Their pathomechanisms are not completely understood, but glutamateinduced excitotoxicity, mitochondrial disturbances and oxidative stress all seem to play crucial roles. The overactivation of glutamate receptors contributes to the hyperexcitability observed in migraine and also to the neurodegenerative process. The kynurenine pathway of the tryptophan metabolism produces the only known endogenous Nmethyl- D-aspartate receptor antagonist, kynurenic acid, which has been proven in different preclinical studies to exert a neuroprotective effect. Influencing the kynurenine pathway might be beneficial in migraine and neurodegenerative diseases, and in the normalization of glutamatergic neurotransmission and the prevention of excitotoxic neuronal damage. The synthesis of kynurenic acid analogues may offer a valuable tool for drug development.