Neuroprotective potential of traditionally used medicinal plants of Manipur against rotenone-induced neurotoxicity in SH-SY5Y neuroblastoma cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Alternanthera sessilis (L.) R. Br. ex DC., Eryngium foetidum L., and Stephania japonica (Thunb.) Miers plants are traditionally used to treat various central nervous system disorders like paralysis, epilepsy, seizure, convulsion, chronic pain, headache, sleep disturbances, sprain, and mental disorders. However, their possible neuroprotective effects have not been evaluated experimentally so far. AIM OF THE STUDY: The study aims to examine the neuroprotective potential of the three plants against cytotoxicity induced by rotenone in SH-SY5Y neuroblastoma cells and assess its plausible mechanisms of neuroprotection. MATERIALS AND METHODS: The antioxidant properties of the plant extracts were determined chemically by DPPH and ABTS assay methods. The cytotoxicity of rotenone and the cytoprotective activities of the extracts were evaluated using MTT assays. Microtubule-associated protein 2 (MAP2) expression studies in cells were performed to assess neuronal survival after rotenone and extract treatments. Mitochondrial membrane potential and intracellular levels of reactive oxygen species were evaluated using Rhodamine 123 and DCF-DA dye, respectively. Catalase, glutathione peroxidase, and superoxide dismutase activities were also measured. Apoptotic nuclei were examined using DAPI staining. Liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (LC-QTOF-MS) analysis of the plant extracts was also performed. RESULTS: The methanol extracts of A. sessilis, S. japonica, and E. foetidum showed excellent free radical scavenging activities. MAP2 expression studies show that A. sessilis and S. japonica have higher neuroprotective effects against rotenone-induced neurotoxicity in SH-SY5Y cells than E. foetidum. Pre-treating cells with the plant extracts reverses the rotenone-induced increase in intracellular ROS. The plant extracts could also restore the reduced mitochondrial membrane potential induced by rotenone treatment and reinstate rotenone-induced increases in catalase, glutathione peroxidase, and superoxide dismutase activities. All the extracts inhibited rotenone-induced changes in nuclear morphology and DNA condensation, an early event of cellular apoptosis. LC-QTOF-MS analysis of the plant extracts shows the presence of neuroprotective compounds. CONCLUSIONS: The plant extracts showed neuroprotective activities against rotenone-treated SH-SY5Y cells through antioxidant and anti-apoptotic mechanisms. These findings support the ethnopharmacological uses of these plants in treating neurological disorders. They probably are a good source of neuroprotective compounds that could be further explored to develop treatment strategies for neurodegenerative diseases like Parkinson's disease.

Breaking the Silence of Tumor Response: Future Prospects of Targeted Radionuclide Therapy.

Therapy-induced tumor resistance has always been a paramount hurdle in the clinical triumph of cancer therapy. Resistance acquired by tumor through interventions of chemotherapeutic drugs, ionizing radiation, and immunotherapy in the patients is a severe drawback and major cause of recurrence of tumor and failure of therapeutic responses. To counter acquired resistance in tumor cells, several strategies are practiced such as chemotherapy regimens, immunotherapy and immunoconjugates, but the outcome is very disappointing for the patients as well as clinicians. Radionuclide therapy using alpha or beta-emitting radionuclide as payload becoming a popular practice for cancer therapy. With the improvement in dosimetric studies, development of high-affinity target molecules and design of several novel chelating agents which provide thermodynamically stable complexes in vivo, the scope of radionuclide therapy has increased by leaps and bounds. Additionally, radionuclide therapy along with the combination of chemotherapy is gaining importance in pre-clinics, which is quite encouraging. Thus, it opens an avenue for newer cancer therapy modalities where chemotherapy, radiation therapy, and immunotherapy are unable to break the silence of tumor response. This article describes, in brief, the causes of tumor resistance and discusses the potential of radionuclide therapy to enhance tumor response.

Association of Dopamine Transporter Gene with Heroin Dependence in an Indian Subpopulation from Manipur.

Dopamine transporter (DAT) or solute carrier family 6 member 3 (SLC6A3) is a transmembrane protein regulating dopaminergic neurotransmission. It has been implicated in playing important roles in the dopaminergic reward pathways, and thus, DAT1 is a strong candidate gene for association studies with heroin dependence. A case-control study involving 279 individuals (147 controls and 132 heroin-dependent cases) was conducted. Ten polymorphisms of the DAT1 (SLC6A3) gene were analysed for its association with heroin dependence. Following the Hardy-Weinberg equilibrium (HWE) test, genetic association analyses were performed for the study groups. The post hoc statistical power of the study was 0.655 (65.5%). Single-nucleotide polymorphism (SNP) rs246997 was found to be significantly associated with heroin dependence at allelic, genotypic, and haplotypic levels. A significant difference in the distribution of 11R allele and 10R/11R genotype of rs28363170 between heroin-dependent cases and controls was also observed. Nominal significance at degrees of freedom (df) = 5 was also observed for rs28363170. Five bimarker-based haplotype combinations were also found to be associated with heroin dependence. For the first time, 13R allele (7R/13R genotype) and 14R allele (7R/14R genotype) were identified for rs3836790 in the population. The study also reports that the 11R allele and 10R/11R genotype of rs28363170 is associated with protection against heroin dependence. 7R and 6R alleles were also found to be the common alleles of rs3836790 in the study population. The study provides evidence for the association of polymorphisms of DAT1 (SLC6A3) with heroin dependence.

A single nucleotide polymorphism in OPRM1(rs483481) and risk for heroin use disorder.

Opioid receptor mu1 (OPRM1) is the target of many opioid drugs, and it is known to have affinity toward both endogenous and exogenous opioids, opiate and opioid analgesic drugs. The present study was undertaken to explore association of single nucleotide polymorphisms (SNPs) in the OPRM1 gene with heroin use disorder. Ten OPRM1 polymorphisms were analyzed in 132 cases and 147 healthy controls. The SNP rs483481 showed significant allelic, genotypic and haplotypic association (Allelic: p-value = 0.003, OR = 1.75, CI = 1.21-2.55) (Genotypic: p-value = 0.003, OR = 1.72, CI = 1.08-2.75) with heroin use disorder. Allelic and genotypic association remained significant even after multiple testing corrections with 1000 permutations. A significant positive correlation between 'Number of times drug abstained' and 'rs483481-AA genotype' (p-value = 0.002; Pearson correlation = 0.265) was also observed. One-way ANOVA analysis demonstrated significant association of rs483481 with 'number of times drug abstained' (F = 4.86, p-value =0.009). 'A' allele and 'AA' genotype of marker rs483481 seem to confer protective effect while 'G' allele and 'GG' genotype potentiates risk for heroin use disorder. OPRM1 is found to be associated with heroin use disorder in the studied Manipuri cohort. The study suggests that individuals with G allele and GG genotypes at rs483481 could be more vulnerable to heroin dependence, and it could be taken into consideration in prevention and intervention programs.