Pre-Clinical Research

RNA therapeutics: revolutionizing drug discovery

2023-10-31T13:36:16+00:00

The astounding rate of advancement in the field of drug discovery and development is impossible to ignore.

A fresh and potent competitor to the conventional method of medication development, which mainly relies on small molecules, is RNA-based treatments. Among them, RNA Interference (RNAi) medicines and Messenger RNA (mRNA) vaccines have become the frontrunners, rewriting the rules for pre-clinical research and the creation of new treatments.

Unlocking the future of drug discovery: navigating challenges and embracing opportunities

2023-09-05T10:12:01+00:00

The world of drug discovery stands at the threshold of an era of unprecedented potential, offering a glimpse into a future where groundbreaking medical breakthroughs could revolutionize healthcare as we know it. However, this journey towards innovation is not without its hurdles, and those at the forefront – the pre-clinical scientists – find themselves navigating a complex terrain of opportunities and challenges....

A comprehensive review of phytochemical components as potential antidepressants

2023-09-05T10:12:11+00:00

Depression is a heterogeneous mood disorder that has been classified and treated in a variety of ways. Despite the fact that a variety of synthetic medications are utilized as conventional treatment for clinically depressed patients, these drugs have side effects that can jeopardize the therapeutic outcome. In recent decades, there has been a rise in research and interest in the psychopharmacology of natural treatments. Thus, it’s worthwhile researching for antidepressants derived from plants that have a demonstrated effect and a favorable benefit-to-risk ratio. By virtue of their medicinal constituents, a variety of medicinal plants and medicines produced from these plants have exhibited antidepressant properties. As a result, major pharmaceutical companies are currently researching plant materials extensively for their possible medical benefit. Depression is caused by low levels of monoamines such as noradrenaline, dopamine, and serotonin in the brain. Therefore, treatments that restore lowered levels of these monoamines in the brain by blocking monoamine oxidase or decreasing reuptake of these neurotransmitters could be beneficial in the treatment of depression. The current review focuses on medicinal plants and plant-based formulations that have been shown to have antidepressant effect in both animal and human studies.

Metal mixture-induced non-transgenic animal model of Alzheimer’s disease: Pros and cons

2019-06-14T10:49:58+00:00

Alzheimer’s disease (AD) is a multifaceted and heterogeneous age-related disease and represents the most common cause of dementia among the elderly. Over the past two decades, transgenic models of AD appreciably contribute to the understanding of the molecular mechanisms involved in the onset and progression of AD. However, transgenic models generally identify with the familial form of AD that accounts for just 5% of AD cases. Thus, non-transgenic models are also essential to thoroughly understand AD pathophysiology. Environmental exposure to heavy metals has been linked to the pathogenesis of the non-familial, sporadic form of AD. This review summarizes our previously published research that showed a mixture of heavy metals, i.e. Arsenic (As), cadmium (Cd) and lead (Pb) at environmentally relevant doses induced AD-parameters and AD-like pathology in the young rats. Our previous findings suggest that the amyloid beta-42 (Aβ1-42) levels in the As+Cd+Pbmixture treated Postnatal-90 day rat brain were comparable with the intracerebroventricular Aβ1-42 infusion rat model, which is well- established non-transgenic model of AD. Additionally, As+Cd+Pb-mixtureinduced Aβ and amyloid precursor protein could be attenuated by known AD-directed drugs, memantine, and donepezil. These findings helped us to conclude that As+Cd+Pb-treated animals could be utilized as a non-transgenic model of AD. This review also summarizes the merits of a nontransgenic animal model of AD, generated through environmental doses of As, Cd and Pb-mixture and its demerits.

The impact of high-fat diet-induced oxidative stress on micro RNA’s in various tissues

2023-09-05T10:12:04+00:00

Stress is the body’s reaction to any kind of injury or danger. It is linked to the production of oxidative free radicals, which are responsible for a variety of acute, chronic, and potentially fatal illnesses and diseases. Free radicals, due to their extreme reactivity, can harm or even kill cells. A High-Fat Diet (HFD) causes “oxidative stress”, which is characterized by an increase in the body’s generation of Reactive Oxygen Species (ROS) as a result of higher levels of triglycerides and Free Fatty Acids (FFA). HFD-induced oxidative stress alters cellular function by affecting transcriptional factors and mitochondrial enzymes (synthesis/inhibition). ROS and FFA damage the receptors of the epithelium, resulting in epithelial damage that impairs cellular function. ROS levels can harm cells by altering the expression of microRNA (miRNA), a sign of RNA damage. MiRNAs are non-coding RNAs found in animals, plants, and some viruses that play a role in the post-transcriptional regulation of gene expression. These three pathways—RNA cleavage, RNA destabilization, and RNA translation into proteins— all play a role in mRNA expression. The miRNA regulates the up- and downregulation of mRNA expression for cellular function, enzyme synthesis, and receptor modulation. MiRNA regulates cell function by maintaining the balance between cellular ROS levels and cellular damage.

Experimental models of migraine both in vitro and in vivo

2019-01-08T17:08:18+00:00

Animal models have been critical to our understanding of the neurobiology of migraine. Model systems have the advantage of being able to control experimental variables to a much greater degree than in human studies. Over the past decade, a number of animal models of migraine have been developed. However, each animal model of migraine has its own merits and demerits. It is imperative that animal model selection shall be based on the neurobiological mechanisms of migraine one chooses to study.

The review summarizes numerous animal models of migraine. In our review, we classified migraine models into five categories: i) models based on anastomoses and isolated blood vessels; ii) models based on neurovascular involvement; iii) Superior Sagittal Sinus stimulation; iv) nitroglycerin induced model; v) genetically modified mouse models. This review discussed above mentioned models covering implications of each model.

Abortifacient activity of Aegle marmelos and Laurus nobilis leaf extracts

2023-09-05T10:12:13+00:00

Rapid elevation of population in India is the one of the major problems, which directly influence the economy of country and may lead to poverty. Government implemented number of family planning programs through the various surgical operations (tubectomy and laproscopy) and oral contraceptives. Usage of oral contraceptive pills may lead serious complications, and may induce congenital abnormalities. The primary goal of this research is to assess the abortifacient activity in rat models of two historically used medicinal plants, Laurus nobilis L. and Aegle marmelos (L.) Corr. Restructure the paragraph as the study included 18 female wistar rats (150-200 g) and six male wistar rats (male wistar rats were used only for copulation). Female rats in proestrous phase were isolated and allowed to mate with males of proven fertility using the mass mating technique in a 3:1 ratio for an overnight. Control animals received an equivalent volume of the dosing vehicle (1% tween 80) orally. Aqueous extract of Laurus nobilis (AQLN) leaves and Ethanolic Extract of Aegle Marmelos leaves (EEAM) at doses of 175 mg/kg and 250 mg/ kg of were orally administrated daily for 10 days from day 0 of pregnancy to day 9. On day 20th of pregnancy, all the animals were sacrificed under euthanasia and the uterine horns were isolated, later they were examined for number of abortifacient sites and deformities of fetuses. The number of live fetuses in animals treated with EEAM at two doses was substantially lower in Group-4 at 175mg/kg (2.63 + 0.36) and Group-5 at 250mg/kg (1.87 + 0.40) compared to the vehicle control group (p 0.05, p 0.01). The survival ratio decreased considerably from 52.2% to 28.8% as the dose increased. Similarly, the abortion rate was higher in group 5 compared to Group-4. AQLN demonstrated to have 100% abortifacient efficacy at 250mg/kg, while EEAM has 83.3%.

Evaluation of metabolism and cytochrome P450 mediated interaction liabilities of naringenin

2023-09-05T10:12:20+00:00

Naringenin is one of the major components of grapefruit juice. It has a broad spectrum of pharmacological activities, and many studies report that grapefruit juice inhibits cytochrome P450 (CYP) 3A4 leading to drug interactions. Naringenin was profiled through various in vitro studies like metabolic stability and glucuronidation in rat and human liver microsomes while, CYP inhibition using human liver microsomes. In addition, pharmacokinetic profiling was conducted upon intravenous (i.v.) and oral administration in rats. Naringenin undergoes both phase I and phase II metabolism in rat liver microsomes, and in human liver microsomes, it is predominantly metabolized by phase II. Glucuronidation which is addition (conjugation) of glucuronic acid to various functional groups is one of the major metabolic pathways of Naringenin. Naringenin, at 1.0 μM and 10.0 μM, did not elicit any appreciable inhibition of the 5 major CYP isoforms (CYP1A2, CYP3A4, CYP2C9, CYP2C19, and CYP2D6). Oral pharmacokinetic studies at 100, 300,and 1000 mg/kg dose and intravenous pharmacokinetic studies at 1 mg/kg dose were performed in male SD rats. Naringenin exhibited very short half-life (0.27 h) and rapid elimination (Clearance=110.65 mL/min/kg) after i.v. administration. There was saturation in Cmax and exposure beyond 100 mg/kg, and the absolute bioavailability was found to be ≤ 5% at the tested oral doses. This present experiment suggests that naringenin does not substantially inhibit CYP3A4 (or any of the tested five isoforms) isoforms per se. Given the minimal involvement of CYP enzymes in the metabolism of naringenin and minimal inhibition of CYP enzymes (IC50> 10 μM), the potential for drug-drug interactions involving CYP substrates and inhibitors is very minimal in humans.

Modulation of haloperidolinduced catalepsy in wistar rats by foxtail millet (Setaria italica)

2023-09-05T10:12:26+00:00

The current study looked at the behavioral and antioxidant activity of Foxtail Millet (FM) against haloperidol-induced catalepsy in Parkinson’s Disease (PD) patients. It has been demonstrated that the antipsychotic drug haloperidol, which has a high capacity to block D2-type receptors, can cause motor impairments similar to those seen in people with PD. Catalepsy can develop when animals are placed in abnormal or unusual postures for an extended period of time. Foxtail millet significantly reduced lipid peroxidation (p 0.001) increased the antioxidant enzymes SOD (p 0.05) and GSH (p 0.05), and significantly improved motor deficits such as catalepsy, motor coordination, and locomotor activity in our study. These results show that foxtail millet can protect against the motor deficits (catalepsy) associated with PD and epilepsy.