Status epilepticus is a neurological disorder that can result in various neuropathological conditions and presentations. Various studies involving animal models have been accomplished to understand and replicating its prominent manifestations including characteristics of related clinical cases. Up to these days, there are variety of methods and techniques to be utilized in inducing this disorder that can be chemically or electrically applied which depending on the experimental designs and targets of the studies. In particular, the chemically induced pilocarpine animal model of status epilepticus is a reliable choice which has evolved for 40 years from its initial discovery back in 1983. Although the development of the model can be considered as a remarkable breakthrough in understanding status epilepticus, several aspects of the model have been improved, throughout the years. Among the major issues in developing this model are the morbidity and mortality rates during induction process. Several modifications have been introduced in the process by different studies to tackle the related problems including application of dose fractionation, adaptation of pilocarpine to lithium-pilocarpine model and utilization of various drugs. Despite all challenges and drawbacks, this model has proven its pertinent and relevance with improvements that have been adapted since it was introduced 40 years ago. In this review, we emphasize on the evolution of this animal model from the beginning until now (1983 - 2023) and the related issues that have made this model still a popular choice in status epilepticus studies.
The pilocarpine animal model of status epilepticus is a well-established, clinically translatable model that satisfies all of the criteria essential for an animal model of status epilepticus: a latency period followed by spontaneous recurrent seizures, replication of behavioural, electrographic, metabolic, and neuropathological changes, as well as, pharmacoresistance to anti-epileptic drugs similar to that observed in human status epilepticus. However, this model is also characterized by high mortality rates and studies in recent years have also seen difficulties in seizure induction due to pilocarpine resistant animals. This can be attributed to differences in rodent strains, species, gender, and the presence of the multi-transporter, P-glycoprotein at the blood brain barrier. The current paper highlights the various alterations made to the original pilocarpine model over the years to combat both the high mortality and low induction rates. These range from the initial lithium-pilocarpine model to the more recent Reduced Intensity Status Epilepticus (RISE) model, which finally brought the mortality rates down to 1%. These modifications are essential to improve animal welfare and future experimental outcomes.
Epilepsy is one of the oldest known neurological disorders and is characterized by recurrent seizure activity. It has a high incidence rate, affecting a broad demographic in both developed and developing countries. Comorbid conditions are frequent in patients with epilepsy and have detrimental effects on their quality of life. Current management options for epilepsy include the use of anti-epileptic drugs, surgery, or a ketogenic diet. However, more than 30% of patients diagnosed with epilepsy exhibit drug resistance to anti-epileptic drugs. Further, surgery and ketogenic diets do little to alleviate the symptoms of patients with pharmacoresistant epilepsy. Thus, there is an urgent need to understand the underlying mechanisms of pharmacoresistant epilepsy to design newer and more effective anti-epileptic drugs. Several theories of pharmacoresistant epilepsy have been suggested over the years, the most common being the gene variant hypothesis, network hypothesis, multidrug transporter hypothesis, and target hypothesis. In our review, we discuss the main theories of pharmacoresistant epilepsy and highlight a possible interconnection between their mechanisms that could lead to the development of novel therapies for pharmacoresistant epilepsy.
Neurodevelopmental disorders are defined as a set of abnormal brain developmental conditions marked by the early childhood onset of cognitive, behavioral, and functional deficits leading to memory and learning problems, emotional instability, and impulsivity. Autism spectrum disorder, attention-deficit/hyperactivity disorder, Tourette syndrome, fragile X syndrome, and Down's syndrome are a few known examples of neurodevelopmental disorders. Although they are relatively common in both developed and developing countries, very little is currently known about their underlying molecular mechanisms. Both genetic and environmental factors are known to increase the risk of neurodevelopmental disorders. Current diagnostic and screening tests for neurodevelopmental disorders are not reliable; hence, individuals with neurodevelopmental disorders are often diagnosed in the later stages. This negatively affects their prognosis and quality of life, prompting the need for a better diagnostic biomarker. Recent studies on microRNAs and their altered regulation in diseases have shed some light on the possible role they could play in the development of the central nervous system. This review attempts to elucidate our current understanding of the role that microRNAs play in neurodevelopmental disorders with the hope of utilizing them as potential biomarkers in the future.
The γ-aminobutyric acid type A receptor (GABA (A) receptor) is a membrane protein activated by the neurotransmitter GABA. Structurally, this major inhibitory neurotransmitter receptor in the human central nervous system is a pentamer that can be built from a selection of 19 subunits consisting of α(1,2,3,4,5 or 6), β (1,2 or 3), γ (1,2 or 3), ρ (1,2 or 3), and δ, π, θ, and ε. This creates several possible pentameric arrangements, which also influence the pharmacological and physiological properties of the receptor. The complexity and heterogeneity of the receptors are further increased by the addition of short and long splice variants in several subunits and the existence of multiple allosteric binding sites and expansive ligands that can bind to the receptors. Therefore, a comprehensive understanding of the structure and function of the receptors is required to gain novel insights into the consequences of receptor dysfunction and subsequent drug development studies. Notably, advancements in computational-aided studies have facilitated the elucidation of residual interactions and exploring energy binding, which may otherwise be challenging to investigate. In this review, we aim to summarize the current understanding of the structure and function of GABA (A) receptors obtained from advancements in computational-aided applications.
Epigenetic alterations associated with cancer have been shown to facilitate tumorigenesis and promote metastasis. In the study of cancer metastasis, epigenetics has been revealed to play a crucial role in supporting tumour immune evasion. As a result, epigenetic drugs have been identified as potential agents to activate anti-tumour immune responses and reverse tumour immunologically tolerant states. Mounting evidence is showing aberrant expression of MHC class I antigen processing molecules in cancers and their upregulation as a potential indicator for anti-tumour immunity. In this study, we demonstrate that the epigenetic drug Trichostatin A (TSA), a histone deacetylase inhibitor, can restore MHC I antigen presentation machinery (MHC I APM) genes in human breast cancer cells (MCF-7). Treatment with TSA resulted in the upregulation of MHC I, B2M, and PSMB9 in MCF-7 monolayer cells, and MHC I, B2M, PSMB9, PSMB8, TAP1, and TAP2 in MCF-7 spheroid cells. Interestingly, treatment with TSA also increased CD274 expression in these cells and enhanced the invasion ability of the MCF-7 spheroid. This aggressive behaviour was confirmed by increased expression of metastatic-related genes, nNav1.5 and MMP1. In summary, although the restoration of MHCIAPM expression was achieved by TSA, the upregulation of metastatic genes and CD274 also enhanced the invasion ability of breast cancer cells. These findings suggest the need for careful consideration when utilizing epigenetic drugs for breast cancer therapy.