CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 19, Issue 10, 2020

1-Methyl-1,2,3,4-tetrahydroisoquinoline-6,7-diol, commonly known as salsolinol, is a compound derived from dopamine. It was first discovered in 1973 and has gained attention for its role in Parkinson’s disease. Salsolinol and its derivatives were claimed to play a role in the pathogenesis of Parkinson’s disease as a neurotoxin that induces apoptosis of dopaminergic neurons due to its structural similarity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its ability to induce Parkinsonism. In this article, we discussed the biosynthesis, distribution and blood-brain barrier permeability of salsolinol. The roles of salsolinol in a healthy brain, particularly the interactions with enzymes, hormone and catecholamine, were reviewed. Finally, we discussed the involvement of salsolinol and its derivatives in the pathogenesis of Parkinson’s disease.

Refractory epilepsy is a type of epilepsy involving seizures uncontrolled by first or second- line anticonvulsant drugs at a regular therapeutic dose. Despite considerable growth in epileptic pharmacotherapy, one-third of the patients are resistant to current therapies. In this, the mechanisms responsible for resistant epilepsy are either increased expulsion of antiepileptic drugs (AEDs) by multidrug resistance (MDR) transporters from the epileptogenic tissue or reduced sensitivity of drug in epileptogenic brain tissue. The difficulty to treat refractory epilepsy is because of drug resistance due to cellular drug efflux, use of drug monotherapy, and subtherapeutic dose administration. Increased expression of Pgp is also responsible for resistance epilepsy or refractory epilepsy. Increased glutamate expression via inhibition of cyclooxygenase-II (COX-II) enzyme also upregulate P-glycoprotein (Pgp) expression and augment instance of recurrent seizures. Peripheral and central inhibition of Pgp is a powerful tool to control this drug resistant epilepsy. Drug resistance primarily involves multidrug resistance (MDR1) gene responsible for encoding P-glycoprotein (Pg- P1 or MDR1). Currently, there is no drug under clinical practice which inhibits MDR1. The present review cites some drugs like Calcium Channel Blockers (CCBs), COX-II inhibitors, and glutamate receptors antagonists that inhibit P-gp. The exploitation of these targets may emerge as a beneficial approach for patients with drug-resistant epilepsy. The present review further highlights the mechanistic role of Pgp in drug-resistant epilepsy, glutamate role in drug efflux, and management approach.

Epilepsy is the second most common neurological disease with abnormal neural activity involving the activation of various intracellular signalling transduction mechanisms. The molecular and system biology mechanisms responsible for epileptogenesis are not well defined or understood. Neuroinflammation, neurodegeneration and Epigenetic modification elicit epileptogenesis. The excessive neuronal activities in the brain are associated with neurochemical changes underlying the deleterious consequences of excitotoxicity. The prolonged repetitive excessive neuronal activities extended to brain tissue injury by the activation of microglia regulating abnormal neuroglia remodelling and monocyte infiltration in response to brain lesions inducing axonal sprouting contributing to neurodegeneration. The alteration of various downstream transduction pathways resulted in intracellular stress responses associating endoplasmic reticulum, mitochondrial and lysosomal dysfunction, activation of nucleases, proteases mediated neuronal death. The recently novel pharmacological agents modulate various receptors like mTOR, COX-2, TRK, JAK-STAT, epigenetic modulators and neurosteroids are used for attenuation of epileptogenesis. Whereas the various molecular changes like the mutation of the cell surface, nuclear receptor and ion channels focusing on repetitive episodic seizures have been explored by preclinical and clinical studies. Despite effective pharmacotherapy for epilepsy, the inadequate understanding of precise mechanisms, drug resistance and therapeutic failure are the current fundamental problems in epilepsy. Therefore, the novel pharmacological approaches evaluated for efficacy on experimental models of epilepsy need to be identified and validated. In addition, we need to understand the downstream signalling pathways of new targets for the treatment of epilepsy. This review emphasizes on the current state of novel molecular targets as therapeutic approaches and future directions for the management of epileptogenesis. Novel pharmacological approaches and clinical exploration are essential to make new frontiers in curing epilepsy.

Background: Tremor is one of the most noticeable features, which occurs during the early stages of Parkinson’s Disease (PD). It is one of the major pathological hallmarks and does not have any interpreted mechanism. In this study, we have framed a hypothesis and deciphered protein- protein interactions between the proteins involved in impairment in sodium and calcium ion channels and thus cause synaptic plasticity leading to a tremor. Methods: Literature mining for retrieval of proteins was done using Science Direct, PubMed Central, SciELO and JSTOR databases. A well-thought approach was used, and a list of differentially expressed proteins in PD was collected from different sources. A total of 71 proteins were retrieved, and a protein interaction network was constructed between them by using Cytoscape.v.3.7. The network was further analysed using the BiNGO plugin for retrieval of overrepresented biological processes in Tremor-PD datasets. Hub nodes were also generated in the network. Results: The Tremor-PD pathway was deciphered, which demonstrates the cascade of protein interactions that might lead to tremors in PD. Major proteins involved were LRRK2, TUBA1A, TRAF6, HSPA5, ADORA2A, DRD1, DRD2, SNCA, ADCY5, TH, etc. Conclusion: In the current study, it is predicted that ADORA2A and DRD1/DRD2 are equally contributing to the progression of the disease by inhibiting the activity of adenylyl cyclase and thereby increases the permeability of the blood-brain barrier, causing an influx of neurotransmitters and together they alter the level of dopamine in the brain which eventually leads to tremor.

Background: Mammalian target of rapamycin (mTOR) has been evidenced as a multimodal therapy in the pathophysiological process of Acute Ischemic Stroke (AIS). However, the pathway that minocycline targets mTOR signaling is not fully defined in the AIS pathogenesis. This study aims at the roles of minocycline on the mTOR signaling in the AIS process and further discovers the underlying mechanisms of minocycline involved in the following change of mTOR signaling-autophagy. Methods: Cerebral ischemia/reperfusion (CIR) rat animal models were established with the transient suture occlusion into the middle cerebral artery. Minocycline (50mg/kg) was given by intragastric administration. The Morris water maze was used to test the cognitive function of animals. Immunohistochemistry and immunofluorescence were introduced for testing the levels of synaptophysin and PSD-95. Western blot was conducted for investigating the levels of mTOR, p-mTOR (Ser2448), p70S6, p-p70S6 (Thr389), eEF2k, p-eEF2k (Ser366), p-eIF4B (Ser406), LC3, p62, synaptophysin and PSD-95. Results: Minocycline prevents the cognitive decline of the MCAO stroke rats. Minocycline limits the expression of p-mTOR (Ser2448) and the downstream targets of mTOR [p70S6, p-p70S6 (Thr389), eEF2k, p-eEF2k (Ser366) and p-eIF4B (Ser406)] (P<0.01), while minocycline has no influence on mTOR. LC3-II abundance and the LC3-II/I ratio were upregulated in the hippocampus of the MCAO stroke rats by the minocycline therapy (P<0.01). p62 was downregulated in the hippocampus from the MCAO stroke rats administrated with minocycline therapy(P<0.01). The levels of SYP and PSD-95 were upregulated in the brain of the MCAO stroke rats administrated with minocycline therapy. Conclusion: Minocycline prevents cognitive deficits via inhibiting mTOR signaling and enhancing the autophagy process, and promoting the expression of pre- and postsynaptic proteins (synaptophysin and PSD-95) in the brain of the MCAO stroke rats. The potential neuroprotective role of minocycline in the process of cerebral ischemia may be related to mitigating ischemia-induced synapse injury via inhibiting the activation of mTOR signaling.