Current Topics in Medicinal Chemistry - Volume 16, Issue 17, 2016

Due to multi-faceted pathology of AD; no drug can seize the progress of the disease, whereas only the symptomatic treatment is available at the moment. Several drug classes to treat AD are available in clinical use, AChEIs being the most prescribed. In addition to AChEIs, secretase enzymes and iron chelators have turned out to be the focus of research and the popular targets in drug discovery against AD. The latest approaches such as immunotherapy, multi-targeted drug ligand design, AChE inhibitors, antioxidants, metal chelators, monoamine oxidase (MAO) inhibitors, antiinflammatory drugs, and N-methyl-D-aspartate (NMDA) inhibitors are currently in use to cure this disease to some extent. But, there is a certain need to develop new drugs to fight with AD, particularly acting on multi-targets or with dual mechanisms of action. In this review, a particular emphasis will be focused on multitargets aiming at AD to design new drug molecules with respect to treatment strategies and preventive measures. Since the underlying pathogenesis of AD is complicated and still under investigation, the attempts to design highly selective and potent agents to treat AD are quite intensively continuing. In this respect, designing novel drugs with dual/multi-acting mechanisms seems to be more rational.

Omega-3 and omega-6 fatty acids are polyunsaturated fatty acids (PUFAs) with multiple double bonds. Linolenic and alpha-linolenic acids are omega-6 and omega-3 PUFAs, precursors for the synthesis of long-chain PUFAs (LC-PUFAs), such as arachidonic acid (omega-6 PUFA), and eicosapentaenoic and docosahexaenoic acids (omega-3 PUFAs). The three most important omega-3 fatty acids are alpha-linolenic, eicosapentaenoic and docosahexaenoic acids, which cannot be synthesized in enough amounts by the body, and therefore they must be supplied by the diet. Omega-3 fatty acids are essential for the correct functioning of the organism and participate in many physiological processes in the brain. Epilepsy is a common and heterogeneous chronic brain disorder characterized by recurrent epileptic seizures leading to neuropsychiatric disabilities. The prevalence of epilepsy is high achieving about 1% of the general population. There is evidence suggesting that omega-3 fatty acids may have neuroprotective and anticonvulsant effects and, accordingly, may have a potential use in the treatment of epilepsy. In the present review, the potential use of omega-3 fatty acids in the treatment of epilepsy, and the possible proposed mechanisms of action are discussed. The present article summarizes the recent knowledge of the potential protective role of dietary omega-3 fatty acids in epilepsy.

Parkinson’s disease is a motor dysfunction that has been widely studied but many of the reports on commercial drugs for the treatment of this disease have afforded some undesirable side effects that generate an extensive and unviable treatment by economic costs and due to the bioavailability of the assayed compounds. At present, some molecules are used as L-DOPA agonists or can change the dopamine concentrations in the CNS. Thus, the use of aporphine-type alkaloids has given a real alternative due to the diverse natural sources where can be isolated or to obtain them by means of conventional syntheses. Isoquinoline alkaloids as liriodenine, phenanthrene-type alkaloids, alkoxy-hydroxyaporphine, aminothiazole-aporphine or lipoic ester aporphine derivatives are some of the examples to be considered in this mini-review, wherein the applied pharmacological effects to reduce the motor disorders and the possible medical properties of these alkaloids on the dopaminergic receptors are analyzed.

According to the epidemiological reports published by the World Health Organization, the proportion of elderly people (over 60 years) will increase from 11% to 22% by 2050 worldwide. This increase will be associated with a growing rate of morbidity and mortality of age-related diseases. Mental and neurodegenerative diseases are important health problems in elderly people. Therefore, recent research has been focused on finding effective neuroprotective agents with low adverse effects. Over the last two decades, much attention has been drawn to plant-derived bioactive compounds as novel therapeutic agents for treatment of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Among them, flavonoid chemical class is known as one of the most bioactive and non-toxic phytochemicals, which are widely found in different herbal medicines and edible plants. Fisetin is one of the most common and bioactive flavonoids which possesses potential neuroprotective effects. Fisetin also enhances learning and memory, decreases neuronal cell death, and suppresses oxidative stress. The present paper aims to critically evaluate the available literature regarding the beneficial effects of fisetin on neurodegenerative diseases, especially AD and PD.. In addition, we provide information regarding the chemistry, sources, bioavailability and clinical impacts of fisetin to provide a broad spectrum for the use of this compound as a new approach to the treatment of AD and PD.

Cannabinoids are found to be very useful in psychiatry because of their antipsychotic properties suggesting a therapeutic use as neuroleptic agents in limiting psychotic diseases. Cannabinoids treatments are both able to reduce the typical symptoms of schizophrenia and to slow down the disease aggravation. In the present review, we reported recent studies supporting the idea that the cannabinoid system may modulate the activity of the striatum and temporal cortex linked to psychosis and schizophrenia. Furthermore, anatomical, electrophysiological, pharmacological and biochemical data suggest that the psychotic disorders related to the impaired cannabinoid system may lead to the development of novel compounds that selectively target specific elements of the cannabinoid system.

Anxiety disorders are the most common mental illnesses affecting human beings. They range from panic to generalized anxiety disorders upsetting the well-being and psychosocial performance of patients. Several conventional anxiolytic drugs are being used which in turn results in several adverse effects. Therefore, studies to find suitable safe medicines from natural sources are being conducted by researchers. The aim of the present study is to comprehensively review phytochemical compounds with well-established anxiolytic activities and their structure-activity relationships as well as neuropsychopharmacological aspects. Results showed that phytochemicals like; alkaloids, flavonoids, phenolic acids, lignans, cinnamates, terpenes and saponins possess anxiolytic effects in a wide range of animal models of anxiety. The involved mechanisms include interaction with γ-aminobutyric acid (GABA)A receptors at benzodiazepine (BZD) and non-BZD sites with various affinity to different subunits, serotonergic 5-hydrodytryptamine (5-HT)1A and 5-HT2A/C receptors, noradrenergic and dopaminergic systems, glycine and glutamate receptors, and Κ-opioid receptor as well as cannabinoid (CB)1 and CB2 receptors. Phytochemicals also modulate the hypothalamo-pituitary-adrenal (HPA) axis, the levels of pro-inflammatory cytokines like interleukin (IL)-2, IL-6, IL-1β and tumor necrosis factor (TNF)-α, and improve brain derived neurotrophic factor (BDNF) levels. Transient receptor potential cation channel subfamily V (TRPV)3, nitric oxide cyclic guanosine monophosphate (NOcGMP) pathway and monoamine oxidase enzymes are other targets of phytochemicals with anxiolytic activity. Taking together, these phytochemicals may be considered as supplements to conventional anxiolytic therapies in order to improve efficacy and reduce adverse effects. Further preclinical and clinical studies are still needed in order to recognize the structure-activity relationships, metabolism, absorption, and neuropsychopharmacological mechanisms of plantderived natural agents.

Neurodegenerative diseases cause a progressive functional alteration of neuronal systems, resulting in a state of dementia which is considered one of the most common psychiatric disorders of the elderly. Dementia implies an irreversible impairment of intellect that increases with age causing alteration of memory, language and behavioral problems. The most common form, which occurs in more than half of all cases, is Alzheimer’s disease, characterized by accumulation of amyloid plaques and neurofibrillary tangles. Neuroinflammation and oxidative stresses have been considered as a hallmark of Alzheimer disease, playing a crucial role in neurotoxicity. For this reason, an adequate antioxidant strategy may improve the treatment of neurodegenerative diseases and dementia. Several studies support the neuroprotective abilities of polyphenolic compounds resulting in neuronal protection against injury induced by neurotoxins, ability to suppress neuroinflammation and the potential to promote memory, learning and cognitive functions. We critically reviewed here the therapeutic potential of pure herbal compounds (e.g., green tea polyphenol (-)- epigallocatechin-3-gallate, resveratrol, curcumin, quercetin and others) and extracts enriched in polyphenols showing the most promising neuroprotective effects. We are also presenting data on the ability of an extract derived from elderberry, Sambucus nigra, possessing elevated polyphenolic content and antioxidant capacity to protect neuronal cells against oxidizing agents.

Resveratrol (3,4',5-trihydroxystilbene) is a naturally occurring phytochemical present in red wine, grapes, berries, chocolate and peanuts. Clinically, resveratrol has exhibited significant antioxidant, anti-inflammatory, anti-viral, and anti-cancer properties. Although resveratrol was first isolated in 1940, it was not until the last decade that it was recognised for its potential therapeutic role in reducing the risk of neurodegeneration, and Alzheimer's disease (AD) in particular. AD is the primary cause of progressive dementia. Resveratrol has demonstrated neuroprotective effects in several in vitro and in vivo models of AD. Apart from its potent antioxidant and anti-inflammatory roles, evidence suggests that resveratrol also facilitates non-amyloidogenic breakdown of the amyloid precursor protein (APP), and promotes removal of neurotoxic amyloid beta (Aβ) peptides, a critical step in preventing and slowing down AD pathology. Resveratrol also reduces damage to neuronal cells via a variety of additional mechanisms, most notably is the activation of NAD+-dependent histone deacetylases enzymes, termed sirtuins. However in spite of the considerable advances in clarifying the mechanism of action of resveratrol, it is unlikely to be effective as monotherapy in AD due to its poor bioavailability, biotransformation, and requisite synergism with other dietary factors. This review summarizes the relevance of resveratrol in the pathophysiology of AD. It also highlights why resveratrol alone may not be an effective single therapy, and how resveratrol coupled to other compounds might yet prove an effective therapy with multiple targets.