Ramu Venkatesan

Phytochemicals that regulate neurodegenerative disease by targeting neurotrophins: a comprehensive review.

Alzheimers disease (AD), characterized by progressive dementia and deterioration of cognitive function, is an unsolved social and medical problem. Age, nutrition, and toxins are the most common causes of AD. However, currently no credible treatment is available for AD. Traditional herbs and phytochemicals may delay its onset and slow its progression and also allow recovery by targeting multiple pathological causes by antioxidative, anti-inflammatory, and antiamyloidogenic properties. They also regulate mitochondrial stress, apoptotic factors, free radical scavenging system, and neurotrophic factors. Neurotrophins such as BDNF, NGF, NT3, and NT4/5 play a vital role in neuronal and nonneuronal responses to AD. Neurotrophins depletion accelerates the progression of AD and therefore, replacing such neurotrophins may be a potential treatment for neurodegenerative disease. Here, we review the phytochemicals that mediate the signaling pathways involved in neuroprotection specifically neurotrophin-mediated activation of Trk receptors and members of p75NTR superfamily. We focus on representative phenolic derivatives, iridoid glycosides, terpenoids, alkaloids, and steroidal saponins as regulators of neurotrophin-mediated neuroprotection. Although these phytochemicals have attracted attention owing to their in vitro neurotrophin potentiating activity, their in vivo and clinical efficacy trials has yet to be established. Therefore, further research is necessary to prove the neuroprotective effects in preclinical models and in humans.

Neuroprotective and Anti-Inflammatory Activities of Allyl Isothiocyanate through Attenuation of JNK/NF-κB/TNF-α Signaling

Allyl isothiocyanate (AITC), present in Wasabia japonica (wasabi), is an aliphatic isothiocyanate derived from the precursor sinigrin, which is a glucosinolate present in vegetables of the Brassica family. Traditionally, it has been used to treat rheumatic arthralgia, blood circulation, and pain. This study focuses on its anti-apoptotic activity through the regulation of lipopolysaccharide (LPS)-induced neuroinflammation. Furthermore, we assessed its neuroprotective efficacy, which it achieves through the upregulation of nerve growth factor (NGF) production. Pretreatment with AITC significantly inhibited inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression, decreased tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), prostaglandin E2 (PGE2), and nitric oxide (NO) production in activated microglia, and increased the nerve growth factor (NGF) and neurite outgrowth in neuroblastoma cells. AITC inhibited the nuclear factor (NF-κB-mediated transcription by modulating mitogen activated protein kinase (MAPK) signaling, particularly downregulating c-Jun N-terminal kinase (JNK) phosphorylation, which was followed by a reduction in the TNF-α expression in activated microglia. This promising effect of AITC in controlling JNK/NF-κB/TNF-α cross-linking maintains the Bcl-2 gene family and protects neuroblastoma cells from activated microglia-induced toxicity. These findings provide novel insights into the anti-neuroinflammatory effects of AITC on microglial cells, which may have clinical significance in neurodegeneration.

Malathion increases apoptotic cell death by inducing lysosomal membrane permeabilization in N2a neuroblastoma cells: a model for neurodegeneration in Alzheimer’s disease

Malathion is an organophosphate with severe neurotoxic effects. Upon acute exposure, malathion initially enhances cholinergic activity by inhibition of acetylcholinesterase, which is its major pathological mechanism. Malathion also induces non-cholinergic neuronal cell death in neurodegenerative conditions; the associated molecular mechanism is not well-characterized. To investigate the molecular mechanism of malathion-induced cell death, N2a mouse neuroblastoma cells were exposed to malathion and cell death-related parameters were examined. Malathion reduced cell viability mainly by apoptosis through mitochondrial dysfunction in N2a cells, as judged by an increase in the level of the pro-apoptotic protein Bax and decrease in the levels of the anti-apoptotic proteins p-Akt and Bcl2, resulting in cytochrome c release and caspase-dependent DNA fragmentation and condensation. Malathion treatment also induced autophagy and lysosomal membrane permeabilization (LMP) in N2a cells. LMP caused a lessening of autophagic flux via inhibition of lysosomal fusion with the autophagosome. LMP-induced cathepsin B release and its proteolytic effect may intensify apoptotic insults. Moreover, malathion-exposed N2a cells showed a marked reduction in the levels of the neuronal marker proteins vascular endothelial growth factor and heart fatty acid binding protein 3, along with diminished neuritogenesis in N2a cells and nerve growth factor secretion in C6 glioma cells. Our data suggest that the non-cholinergic effect of malathion may be mediated by apoptotic cell death via LMP induction in N2a cells. Malathion-treated N2a cells can be utilized as an in vitro model system to screen natural and new chemical drug candidates for neurodegenerative diseases such as Alzheimer’s disease.

Dietary supplementation with a fermented barley and soybean mixture attenuates UVB-induced skin aging and dehydration in hairless mouse skin

This study evaluated the protective effects of dietary supplementation with a fermented barley and soybean mixture (BS) on ultraviolet (UV) B-induced photoaging in hairless mice. Skin aging-related parameters and protein levels related to skin wrinkles and moisturization in mice were analyzed. The BS reduced wrinkle formation, skin thickening, transepidermal water loss, and matrix metalloproteinases-1 expression in skin. Skin hydration and pH were increased in the BS group. BS attenuated filaggrin expression as well as free amino acid and glycerol production. BS increased superoxide dismutase activity as well as increased expression of nuclear factor (erythroid-derived 2)-like 2, procollagen type-I, and decreased erythema. These results suggest that BS protects against photoaging induced by UVB in vivo, indicating the potential of such mixtures as anti-photoaging dietary supplementation.

Identification of novel acetylcholinesterase inhibitors designed by pharmacophore-based virtual screening, molecular docking and bioassay

In this study, pharmacophore based 3D QSAR models for human acetylcholinesterase (AChE) inhibitors were generated, with good significance, statistical values (r2training = 0.73) and predictability (q2training = 0.67). It was further validated by three methods (Fischer’s test, decoy set and Güner-Henry scoring method) to show that the models can be used to predict the biological activities of compounds without costly and time-consuming synthesis. The criteria for virtual screening were also validated by testing the selective AChE inhibitors. Virtual screening experiments and subsequent in vitro evaluation of promising hits revealed a novel and selective AChE inhibitor. Thus, the findings reported herein may provide a new strategy for the discovery of selective AChE inhibitors. The IC50 value of compounds 5c and 6a presented selective inhibition of AChE without inhibiting butyrylcholinesterase (BChE) at uM level. Molecular docking studies were performed to explain the potent AChE inhibition of the target compounds studies to explain high affinity.

Lactucopicrin potentiates neuritogenesis and neurotrophic effects by regulating Ca(2+)/CaMKII/ATF1 signaling pathway.

ETHNO-PHARMACOLOGICAL RELEVANCE Lactucopicrin is one of constitutes in Cichorium intybus L, which is commonly known as chicory in worldwide. It has been used for traditional usage such as antianalgesics, antidepressants and antihyperglycemics AIM OF STUDY: We investigated the neurotrophin-mediated neuroprotective effect of lactucopicrin in in vitro and examined for the underlying mechanism. MATERIALS AND METHOD To verify the neuroprotective effect of lactucopicrin, we investigated the inhibitory AChE activity, neurite outgrowth-related downstream signaling in murine neuroblastoma N2a and neurotrophins secretion in rat C6 glioma cells. RESULTS Lactucopicrin inhibited the AChE activity and increased intracellular Ca2+ levels with a substantial rise in muscarinic acetylcholine receptor M1 (CHRM1) expression in N2a cells. Moreover, lactucopicrin actively promoted neurite outgrowth via Ca2+-mediated activation of Ca2+/calmodulin-dependent protein kinase-II (CaMKII). It further activates transcription factor 1 (ATF1) along with modulating the levels of tropomyosin receptor kinase A, extracellular signal-regulated kinase 1 and 2, AKT, and synaptophysin 1 in N2a cells. Additionally, the levels of neurotrophins including NGF, BDNF, and NT3 were increased by treatment of lactucopicrin in C6 cells. The effects of lactucopicrin on NGF secretion and neuritogenesis were maintained even in the presence of phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002, indicating that lactucopicrin exerts its effect on neuritogenesis in a PI3K-independent manner. CONCLUSION Our results suggest that the natural compound lactucopicrin may be a promising neurotrophin-mediated neuroprotective candidate for neurodegenerative diseases.

Gnetol, a Resveratrol Derivative Ameliorates Malathion-Induced Neurotoxicity through Modulating Lysosomal Membrane Permeabilization in N 2 a Cells

Malathion is a highly neurotoxic organophosphate (OP) pesticide which is in wide use. It is known for its high toxicity to insects, which is caused by inhibition of acetylcholinesterase activity, and for being neurotoxic to humans and other mammals. The present study mainly focused on potential effect of 2,3’,5’,6-tetrahydroxy-trans-stilbene (gnetol) on malathion-induced neuronal cell death in N2a mouse neuroblastoma cells. Malathion activated lysosomal cathepsin B release, resulting in defective autophagy and induction of apoptotic cell death. Interestingly, gnetol (5, 10, and 20 μM) protected cells from apoptosis by regulating heart fatty acid binding protein 3 (hFABP3) and vascular endothelial growth factor (VEGF) expression, leading to improvements in the cellular and nuclear morphological changes induced by malathion. Gnetol induced autophagy by reducing lysosomal cathepsin B release as assessed by immunofluorescence staining, which ameliorated apoptotic cell death in N2a cells. Furthermore, the neurite outgrowth and the NGF level were upregulated by gnetol treatment. Taken together, gnetol, a resveratrol derivative, may protect neuronal cells against malathion-mediated apoptosis and potentiate neuritogenesis. Graphical Abstract Schematic representation of the proposed role of gnetol on lysosomal destabilization in malathion-induced apoptosis in N2a neuroblastoma cells