Recent Patents on CNS Drug Discovery (Discontinued) - Volume 7, Issue 3, 2012

Neurodegeneration is a term used to describe progressive deterioration of structure and/or function of neurons that affects different parts of the central nervous system and leads to eventual death. Neurodegenerative diseases include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Down's syndrome (DS), multiple sclerosis (MS), glaucoma, age-related macular degeneration (AMD), and diabetic encephalopathy (DE). Although the initial events that trigger these disorders may be different from each other, they share similar biochemical reactions that lead to neurodegeneration. Curcuminoids, polyphenol compounds from turmeric (Curcuma longa), possess diverse biological properties that modulate debilitating biochemical processes involved in AD that include attenuation of mitochondrial dysfunction-induced oxidative stress and inflammatory responses to inflammatory cytokines, COX-2, and iNOS. Curcuminoids also bind to β-amyloid (Aβ) plaques to inhibit amyloid accumulation and aggregation in the brain, in addition to inhibiting the toxic Aβ oligomer formation and oligomer-dependent Aβ toxicity. These properties can be further elaborated to DS, glaucoma and AMD. Curcuminoids also prevent α-synuclein aggregation in PD; attenuate ROS-induced COX-2 expression in ALS; ameliorate the symptoms of MS, DE and traumatic brain injury, in addition to neurodamages caused by heavy metal poisoning. These results demonstrate curcuminoids may be potentially effective therapeutic means to treat neurodegenerative diseases. A bulk of patents discloses methods to improve bioavailability of curcuminoids for therapeutic development. This review provides a comprehensive description on the current progress on curcuminoids against neurodegenerative diseases.

It is evident that brain aging engages changes in biological systems linked to synaptic function and cell metabolism and in the capacity to cope with different stresses that are either idiopathic in nature, or subject to environmental insults. In a substantial segment of the aging population there is a pathological transition to cognitive and behavioral dysfunction and thus, age constitutes the primary risk factor for Alzheimer's disease and other neurodegenerative disorders. To address the etiological complexity of aging and age-associated conditions, a new paradigm gaining increasing acceptance considers the use of multi-targeted ligands or combination of drugs to modulate several targets at once. During the past years intensive efforts are dedicated to the implementation of life style habits such as exercise and dietary compounds/ supplements in combination with symptomatic treatment drugs to improve age-related cognitive decline and to attenuate motor and neurological dysfunction in neurodegenerative diseases. The catechin polyphenols constituents of green tea, which were for long time regarded merely as dietary antioxidants, have caught our and other scientist's attention because of their diverse pharmacological activities, which have been allied to a possible beneficial action on brain health. This review will elaborate on the impact of nutritional supplementation on brain function in general, and provide a compilation of the most updated literature on epidemiology, clinical and animal studies with green tea polyphenols in ageassociated cognitive decline and in fighting neurodegenerative diseases. To conclude, a future perspective on the utility and assigned patents with green tea constituents will be presented.

Modulation of NF-E2 related factor 2 (Nrf2) has been shown in several neurodegenerative disorders. The overexpression of Nrf2 has become a potential therapeutic avenue for various neurodegenerative disorders such as Parkinson, Amyotrophic lateral sclerosis, and Alzheimer’s disease. The expression of phase II detoxification enzymes is governed by the cis-acting regulatory element known as antioxidant response element (ARE). The transcription factor Nrf2 binds to ARE thereby transcribing multitude of antioxidant genes. Keap1, a culin 3-based E3 ligase that targets Nrf2 for degradation, sequesters Nrf2 in cytoplasm. Disruption of Keap1-Nrf2 interaction or genetic overexpression of Nrf2 can increase the endogenous antioxidant capacity of the brain thereby rendering protection against oxidative stress in neurodegenerative disorders. This review primarily focuses on recent patents that target Nrf2 overexpression as a promising therapeutic strategy for the treatment of neurodegenerative disorders.

Oxidative stress and glutathione (GSH) depletion are both recognized as significant contributors to the pathogenesis of many devastating neurodegenerative diseases. In particular, mitochondrial dysfunction leads to the aberrant production and accumulation of reactive oxygen species (ROS), which are capable of oxidizing key cellular proteins, lipids, and DNA, ultimately triggering cell death. In addition to other roles that it plays in the cell, GSH functions as a critical scavenger of these ROS. Therefore, GSH depletion exacerbates cell damage due to free radical generation. Strategies that increase or preserve the levels of intracellular GSH have been shown to act in a neuroprotective manner, suggesting that augmentation of the available GSH pool may be a promising therapeutic target for neurodegeneration. This review discusses the capacity of a cystine-rich, whey protein supplement (Immunocal®) to enhance the de novo synthesis of GSH in neurons, and highlights its potential as a novel therapeutic approach to mitigate the oxidative damage that underlies the pathogenesis of various neurodegenerative diseases. Additionally, this review discusses various patents from 1993 to 2012 both with Immunocal® and other methods that modulate GSH in neurodegeneration.

Schizophrenia is most likely a neurodevelopmental disorder with a characteristic delayed onset of symptoms occurring usually during transition from adolescence to adulthood. Recent studies revealed that both genetic and environmental risk factors for the disease disturb not only embryonic, but also postnatal neurogenesis, possible contributing to neurochemical alterations associated with schizophrenia. Several recent patents proposed therapeutic interventions in schizophrenia by increasing postnatal neurogenesis. It remains, however, unclear, how such pro-neurogenic interventions could ameliorate alterations in neurotransmitter systems associated with the disease, such as the dopamine system. Here we review these patents in the context of the existent data about postnatal neurogenesis in the subventricular zone in rodents and primates. We discuss also in light of a recently proposed theoretical model the possible relevance of disturbed neurogenesis for the dopamine system, focusing on the dopamine receptors associated with neurogenesis, the D3 receptors, and a D3-expressing structure derived from the subventricular zone, the Islands of Calleja. Finally, we discuss these findings in the light of molecular imaging studies in early schizophrenia.

Most studies in this journal describe recent patents. The present study only has one such reference. Instead, we hope that its contents will trigger investigation of antidepressant drugs along the suggested lines and lead to ensuing patent applications - first and foremost by more focus on astrocytes. Clinical research has already pointed towards the importance of these cells, which account for one quarter of brain cortical volume and at least as much of its oxidative metabolism. Astrocytes express a multitude of receptors, including 5-HT2B receptors. In cultured astrocytes acute treatment with any of the five SSRIs, fluoxetine, fluvoxamine, sertraline, paroxetine, and citalopram, stimulates equipotently and with sufficient affinity to be therapeutically relevant, the 5-HT2B receptor. Following EGF receptor transactivation and a resultant autocrine HB-EGF stimulation, these drugs activate two interdependent signal pathways i) the Ras-Raf-Mek-ERK phosphorylation pathway and ii) the PI3K-AKT-GSK-3β pathway, eventually altering gene expression. Chronic treatment with fluoxetine upregulates gene expression of cPLA2, ADAR2, GluK2 and 5-HT2B receptors, and RNA editing of the later two in cultured astrocytes and in astrocytes obtained by fluorescence-activated cell sorting of cells from fluoxetinetreated mice. Chronic treatment also down-regulates the Gq-protein-coupled receptor-induced increase of intracellular Ca2+ by inhibiting TRPC function, compromising astrocytic Ca2+ re-filling. This affects glycogenolysis and several steps in the signal pathways. Since astrocytes in the mature brain and in our cultures do not express SERT, both acute and chronic effects in cultured astrocytes must be directly mediated by 5-HT2B receptor activation.