Neurodegenerative Disorder-Targeting Compound 1

Sirtuin activators and inhibitors

Sirtuins 1-7 (SIRT1-7) belong to the third class of deacetylase enzymes, which are dependent on NAD(+) for activity. Sirtuins activity is linked to gene repression, metabolic control, apoptosis and cell survival, DNA repair, development, inflammation, neuroprotection, and healthy aging. Because sirtuins modulation could have beneficial effects on human diseases there is a growing interest in the discovery of small molecules modifying their activities. We review here those compounds known to activate or inhibit sirtuins, discussing the data that support the use of sirtuin-based therapies. Almost all sirtuin activators have been described only for SIRT1. Resveratrol is a natural compound which activates SIRT1, and may help in the treatment or prevention of obesity, and in preventing tumorigenesis and the aging-related decline in heart function and neuronal loss. Due to its poor bioavailability, reformulated versions of resveratrol with improved bioavailability have been developed (resVida, Longevinex(?) , SRT501). Molecules that are structurally unrelated to resveratrol (SRT1720, SRT2104, SRT2379, among others) have been also developed to stimulate sirtuin activities more potently than resveratrol. Sirtuin inhibitors with a wide range of core structures have been identified for SIRT1, SIRT2, SIRT3 and SIRT5 (splitomicin, sirtinol, AGK2, cambinol, suramin, tenovin, salermide, among others). SIRT1 inhibition has been proposed in the treatment of cancer, immunodeficiency virus infections, Fragile X mental retardation syndrome and for preventing or treating parasitic diseases, whereas SIRT2 inhibitors might be useful for the treatment of cancer and neurodegenerative diseases.

The emerging role of the sigma-1 receptor in autophagy: hand-in-hand targets for the treatment of Alzheimer's

Introduction: Autophagy is a cellular catabolic mechanism that helps clear damaged cellular components and is essential for normal cellular and tissue function. The sigma-1 receptor (σ-1R) is a chaperone protein involved in signal transduction, neurite outgrowth, and plasticity, improving memory, and neuroprotection. Recent evidence shows that σ-1R can promote autophagy. Autophagy activation by the σ-1Rs along with other neuroprotective effects makes it an interesting target for the treatment of Alzheimer's disease. AF710B, T-817 MA, and ANAVEX2-73 are some of the σ-1R agonists which have shown promising results and have entered clinical trials. These molecules have also been found to induce autophagy and show cytoprotective effects in cellular models.
Areas covered: This review provides insight into the current understanding of σ-1R functions related to autophagy and their role in alleviating AD.
Expert opinion: We propose a mechanism through which the activation of σ-1R and autophagy could alter amyloid precursor protein processing to inhibit amyloid-β production by reconstituting cholesterol and gangliosides in the lipid raft to offer neuroprotection against AD. Future AD treatment could involve the combined targeting of the σ-1R and autophagy activation. We suggest that future studies investigate the link between autophagy the σ-1R and AD.

Melatonin Receptor as a Drug Target for Neuroprotection

Background: Melatonin, a neurohormone secreted from the pineal gland, circulates throughout the body and then mediates several physiological functions. The pharmacological effects of melatonin can be mediated through its direct antioxidant activity and receptor-dependent signaling.
Objective: This article will mainly review receptor-dependent signaling. Human melatonin receptors include melatonin receptor type 1 (MT1) and melatonin receptor type 2 (MT2), which are widely distributed throughout the brain.
Result: Several lines of evidence have revealed the involvement of the melatonergic system in different neurodegenerative diseases. Alzheimer's disease pathology negatively affects the melatonergic system. Melatonin effectively inhibits β-amyloid (Aβ) synthesis and fibril formation. These effects are reversed by pharmacological melatonin receptor blockade. Reductions in MT1 and MT2 expression in the amygdala and substantia nigra pars compacta have been reported in Parkinson's disease patients. The protective roles of melatonin against ischemic insults via its receptors have also been demonstrated. Melatonin has been reported to enhance neurogenesis through MT2 activation in cerebral ischemic/reperfusion mice. The neurogenic effects of melatonin on mesenchymal stem cells are particularly mediated through MT2.
Conclusion: Understanding the roles of melatonin receptors in neuroprotection against diseases may lead to the development of specific analogs with specificity and potency greater than those of the original compound. These successfully developed compounds may serve as candidate preventive and disease-modifying agents in the future.

2-(4'-Dimethylaminophenyl)-6-[125I]iodobenzothiazole

Alzheimer’s disease (AD) is a major neurodegenerative disease associated with an irreversible decline of mental functions and with cognitive impairment (1). It is characterized by the presence in the brain of senile plaques of β-amyloid (Aβ) peptides with intracellular neurofibrillary tangles of filaments that contain the hyperphosphorylated protein tau (2, 3). Accelerated deposition of Aβ deposits seems to be a key risk factor associated with AD, and although the mechanisms of the disease are still not fully understood, reducing the deposition of amyloid plaques seems to benefit patients.

Several radioligands have been developed (4-6) and tested in humans as in vivo diagnostic tools for imaging and measuring the formation of Aβ deposits (6). The first agent successfully used in human studies was [¹⁸F]FDDNP (7), a malonitrile derivative found to bind to both neurofibrillary tangles and Aβ plaques. The second successful attempt was made with [¹¹C]PIB (8), also known as Pittsburgh Compound B or [¹¹C]6-OH-BTA-1, which showed marked retention in areas of the cortex known to contain substantial amounts of Aβ deposits. The third PET radioligand successfully tested in humans was [¹¹C]4-N-methylamino-4?-hydroxystilbene, a stilbene derivative commonly named [¹¹C]SB-13 that exhibited good binding affinities for Aβ aggregates in vitro, moderate lipophilicity, high initial brain uptake in the normal rat cortex, and a rapid washout (9).

Benzofuran derivatives labeled with radioactive iodine have shown very good binding affinities for Aβ aggregates and good brain penetration (10). Unfortunately, their level of nonspecific binding was found to be very high, which makes them unsuitable for in vivo plaque imaging. However, [¹²⁵I]IMPY displayed good initial brain uptake and rapid washout from normal mouse brain and postmortem AD brain sections (11). Several conjugated thioflavin compounds based on benzothiazole have been shown to bind specifically to amyloid plaques. However, the thioflavins contain an ionic quaternary amine that is permanently charged and unfavorable to brain uptake. For that reason, several alternatives that use neutral derivatives have been synthesized and are currently being evaluated as potential ligands for imaging Aβ deposits in the AD brain. One of them, 2-(4'-dimethylaminophenyl)-6-[¹²⁵I]iodobenzothiazole ([¹²⁵I]TZDM) is currently being studied both in vitro and in vivo (12).

DJ-1/PARK7: A New Therapeutic Target for Neurodegenerative Disorders

DJ-1, encoded in a causative gene of familial Parkinson's disease (PARK7), has multiple functions: it works as an antioxidant, in transcriptional regulation, as a molecular chaperone and in protein degradation. Three types of pathogenic mutants of DJ-1 (M26I, D149A and L166P) have been reported to disrupt proper structures and lead to a loss of function. DJ-1 receives oxidation at the cysteine residue, and the degree of oxidation at the C106 residue determines DJ-1 activity. In this decade, DJ-1 has been reported to suppress the progression of various neurodegenerative disorders in animal models. The administration of recombinant wild-type DJ-1 protein suppresses the neuronal loss associated with both Parkinson's disease and ischemic stroke in rats. Furthermore, in studies focused on DJ-1 as the therapeutic target, compounds that have the capacity of binding to DJ-1 at the C106 residue have been reported to exert therapeutic effects on various neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and ischemic stroke. DJ-1 and DJ-1-targeting molecules/compounds will be useful therapeutic targets for various neurodegenerative disorders due to their various functions such as antioxidant capacity, chaperone function and as a proteolytic pathway.