AbstractA reliable and efficient in vitro model is needed to screen drugs for Alzheimer's disease (AD), as many drugs are currently in the developmental stage. To address this, we developed an in vitro model using amniotic membrane‐derived mesenchymal stem cells (AM‐MSCs) to screen novel drugs for AD. We differentiated AM‐MSCs into neurons and degenerated them using beta amyloid1‐42 (Aß). We then tested AD drugs, which are commercially available such as donepezil, rivastigmine, memantine, citicoline, and two novel drugs, that is, probucol, an anti‐hyperlipidaemic drug, and NMJ‐2, a cinnamic acid analogue for their potential to protect the cells against neurodegeneration. We used gene expression and immunofluorescence staining to assess the neuroprotective ability of these drugs. We also measured the ability of these drugs to reduce lactate dehydrogenase, reactive oxygen species, and nitric oxide levels, as well as their ability to stabilize the mitochondrial membrane potential and increase acetylcholine (ACh) levels. The AD drugs and novel drugs reduced cytotoxicity and oxidative stress, stabilized mitochondrial membrane potential, and restored ACh levels. Furthermore, they reduced BACE1 expression, with a concomitant increase in the expression of cholinergic markers. This AM‐MSCs‐based AD‐like model has immense potential to be an accurate human model and an alternative to animal models for testing a large number of lead compounds in a short time. Our results also suggest that the novel drugs probucol and NMJ‐2 may protect against Aß‐induced neurodegeneration.

2023-11-01·European Journal of Pharmacology

Novel HDAC inhibitors provide neuroprotection in MPTP-induced Parkinson's disease model of rats

Article

作者: Rao, C Mallikarjuna ; Kumar, Gautam ; Meka, Sai Teja ; Birangal, Sumit Raosaheb ; Bojja, Sree Lalitha

Parkinson's Disease (PD) is the most rapidly growing neurological disorder globally in terms of disability and mortality. While symptomatic treatment is available for PD, there is a critical unmet need for effective disease-modifying therapies. Recently, histone deacetylase inhibitors (HDACi), an important class of epigenetic modulators grabbed significant attention as drug targets for neurodegenerative diseases including PD. In this regard, novel pan-HDACi, cinnamyl sulphonamide hydroxamate derivatives (NMJ-2 and NMJ-3), synthesized and characterized in our laboratory, were screened for neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rat model of PD. Twenty-four hours after the bilateral intranigral injection of MPTP, rats were administered orally with NMJ-2 or NMJ-3 (150 mg/kg) daily for 30 days. MPTP administration resulted in a marked rise in lipid peroxidation, and interleukin-1β concentration accompanied by reduced tyrosine hydroxylase and dopamine levels in the striatum compared to the sham group. These biochemical changes were associated with functional motor and non-motor deficits as revealed by loss of motor coordination (rota rod test), impaired grip strength (beam walk test), enhanced rigidity (catalepsy scores), loss of memory (novel object recognition test) and depressive-like behaviour (forced swim test). However, oral treatment with NMJ-2 or NMJ-3, or valproic acid for 30 days significantly attenuated the PD-induced adverse changes in motor and non-motor functions by ameliorating the oxidative stress as well as inflammation, and restoring the dopamine levels in the striatum comparable to the valproic acid group. These results suggest that targeting HDACi could be a rational therapeutic strategy for the development of disease-modifying therapies for PD.

2016-06-01·Chemico-Biological Interactions2区 · 医学

An appraisal of cinnamyl sulfonamide hydroxamate derivatives (HDAC inhibitors) for anti-cancer, anti-angiogenic and anti-metastatic activities in human cancer cells

2区 · 医学

Article

作者: Kumar, Nitesh ; Shoja, M H ; Nayak, Pawan G ; Reddy, Neetinkumar D ; Rao, C Mallikarjuna ; Biswas, Subhankar

Multiple genetic mutations along with unusual epigenetic modifications play a major role in cancer development. Histone deacetylase (HDAC) enzyme overexpression observed in the majority of cancers is responsible for tumor suppressor gene silencing and activation of proto-oncogenes to oncogenes. Cinnamic acid derivatives exhibit anti-cancer potential through HDAC enzyme inhibition. We have synthesized a few cinnamyl sulfonamide hydroxamate derivatives (NMJ-1, -2 and -3) by already published in-house procedures and their purity, and chemical characterization were performed by NMR, mass spectrometry and elemental analysis. The anti-cancer activities were also evaluated against colon cancer. The rationale for synthesis was based on bioisosterism concept. To take the work forward, these compounds were considered for in vitro anti-angiogenic and anti-metastatic activities in cancer cells. The effectiveness of these compounds was determined by SRB assay. The compounds showed cancer cell cytotoxicity (IC50 range of 5.7 ± 0.43 to 20.5 ± 1.9 μM). The mechanism of compound-induced cell death involves an intrinsic apoptosis pathway which was supported by the following: increase in apoptotic index, arrest in cell cycle at G2/M phase, increase in annexin V binding and induction of p21(Waf1/Cip1) expression in the treated cells. Further, their target modulating effect, measured as the expression of acetyl-H3 histone and acetyl α-tubulin was determined by Western blots. Hyper acetylation of H3 histone and α-tubulin were observed. Furthermore, increased expression of cleaved caspase-3, cleaved PARP, total Bad was estimated by ELISA. The anti-angiogenic effect was examined through cobalt (II) chloride (CoCl2)-induced HIF-1α expression, where the compounds reduced the expression of induced HIF-1α. In addition, their anti-metastatic ability was determined through phorbol-12-myristate-13-acetate (PMA)-induced expression of MMP-2 and -9 by Western blotting and gelatin zymography. Inhibition of malignant cell migration was assessed by scratch wound assay. The compounds showed a decrease in cell migration and inhibition of induced MMP-2 and MMP-9 expression. NMJ-2 exhibited comparable activity to that of standard SAHA. Our findings indicate that NMJ series of compound have potent in vitro anti-cancer, anti-angiogenic and anti-metastatic activity through HDAC enzyme inhibition.

100 项与 NMJ-2 相关的药物交易

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