Pharmacology/Drug Development

Neurodegenerative disorders, which are defined by the breakdown of neurons over time, are affecting an increasing number of people. Stroke, Alzheimer's, Parkinson's, Multiple Sclerosis, Migraine, and Amyotrophic Lateral Sclerosis are just a few examples of brain disorders that have no cure. Besides, there is a huge demand for drugs that can cure the diseases mentioned above because the majority of the medications we use to treat them only alleviate diseases. Different neurological disorders have responded satisfactorily to the pharmacological effects of medicinal plants. Despite the numerous multiple types of plants in the world, only a small number of them have been investigated for neurological disorders. As a result, there are many opportunities in this area for further research on plants and their bioactive chemicals. The search for natural therapeutic alternatives that promote faster healing and adverse effects avoidance has gained popularity in recent years. The aim of this mini-review is to explore some natural products that have strong therapeutic effects on neurodegenerative disorders such as Stroke, Alzheimer's Disease, Parkinson's Disease, Multiple Sclerosis, Migraine, Amyotrophic Lateral Sclerosis, and others. We have also shown the safety of natural products to improve their appropriate usage in neurological disorders from recent literature.

Low back pain is a major cause of disability worldwide that declines the quality of life; it poses a substantial economic burden for the patient and society. Intervertebral disc (IVD) degeneration (IDD) is the main cause of low back pain, and it is also the pathological basis of several spinal degenerative diseases, such as intervertebral disc herniation and spinal stenosis. The current clinical drug treatment of IDD focuses on the symptoms and not their pathogenesis, which results in frequent recurrence and gradual aggravation. Moreover, the side effects associated with the long-term use of these drugs further limit their use. The pathological mechanism of IDD is complex, and oxidative stress and inflammation play an important role in promoting IDD. They induce the destruction of the extracellular matrix in IVD and reduce the number of living cells and functional cells, thereby destroying the function of IVD and promoting the occurrence and development of IDD. Phytochemicals from fruits, vegetables, grains, and other herbs play a protective role in the treatment of IDD as they have anti-inflammatory and antioxidant properties. This article reviews the protective effects of phytochemicals on IDD and their regulatory effects on different molecular pathways related to the pathogenesis of IDD. Moreover, the therapeutic limitations and future prospects of IDD treatment have also been reviewed. Phytochemicals are promising candidates for further development and research on IDD treatment.

Emerging information suggests a potential role of medicinal cannabis in pain medication in addition to enhancing immune functions. Endometriosis is a disease of women of reproductive age associated with infertility and reproductive failure as well as chronic pain of varying degrees depending on the stage of the disease. Currently, opioids are being preferred over nonsteroidal anti-inflammatory drugs (NSAID) due to the latter's side effects. However, as the opioids are becoming a source of addiction, additional pain medication is urgently needed. Cannabis offers an alternative therapy for treating the pain associated with endometriosis. Information on the use and effectiveness of cannabis against endometriotic pain is lacking. Moreover, expression of receptors for endocannabinoids by the ovarian endometriotic lesions is not known. The goal of this study was to examine whether cannabinoid receptors 1 and 2 (CB1 and CB2) are expressed by ovarian endometriotic lesions. Archived normal ovarian tissues, ovaries with endometriotic lesions, and normal endometrial tissues were examined for the presence of endometrial stromal cells using CD10 (a marker of endometrial stromal cells). Expression of CB1 and CB2 were determined by immunohistochemistry, immunoblotting, and gene expression studies. Intense expression for CB1 and CB2 was detected in the epithelial cells in ovarian endometriotic lesions. Compared with stroma in ovaries with endometriotic lesions, the expression of CB1 and CB2 was significantly higher in the epithelial cells in endometriotic lesions in the ovary ( < 0.0001 and < 0.05, respectively). Immunoblotting and gene expression assays showed similar patterns for CB1 and CB2 protein and (gene encoding CB1) and (gene encoding CB2) gene expression. These results suggest that ovarian endometriotic lesions express CB1 and CB2 receptors, and these lesions may respond to cannabinoids as pain medication. These results will form a foundation for a clinical study with larger cohorts.

The use of intrathecal drug delivery for chronic and cancer pain medicine has been established for decades. However, optimization and utilization of this technique still lag behind other modalities for pain control. Some of this may be due to variability of surgical technique, medication usage and education. It is currently unclear on whether or not practitioners follow available algorithms for the use of intrathecal drug delivery systems.

Local anesthetics with long-lasting effects and selectivity for nociceptors have been sought over the past decades. In this study, we investigated whether amiodarone, a multiple channel blocker, provides long-lasting local anesthesia and whether adding a TRPV1 channel activator selectively prolongs sensory anesthetic effects without prolonging motor blockade. Additionally, we examined whether amiodarone provides long-lasting analgesic effects against inflammatory pain without TRPV1 channel activator co-administration. In the sciatic nerve block model, 32 adult C57BL/6J mice received either bupivacaine, amiodarone with or without capsaicin (a TRPV1 agonist), or vehicle peri-sciatic nerve injection. Sensory and motor blockade were assessed either by pinprick and toe spread tests, respectively. In another set of 16 mice, inflammatory pain was induced in the hind paw by zymosan injection, followed by administration of either amiodarone or vehicle. Mechanical and thermal sensitivity and paw thickness were assessed using the von Frey and Hargreaves tests, respectively. The possible cardiovascular and neurological side effects of local amiodarone injection were assessed in another set of 12 mice. In the sciatic nerve block model, amiodarone produced robust anesthesia, and the co-administration of TRPV1 agonist capsaicin prolonged the duration of sensory blockade, but not that of motor blockade [complete sensory block duration: 195.0 ± 9.8 min vs. 28.8 ± 1.3 min, F (2, 21) = 317.6, < 0.01, complete motor block duration: 27.5 ± 1.6 min vs. 21.3 ± 2.3 min, F (2, 22) = 11.1, = 0.0695]. In the zymosan-induced inflammatory pain model, low-dose amiodarone was effective in reversing the mechanical and thermal hypersensitivity not requiring capsaicin co-administration [50% withdrawal threshold at 8 h (g): 0.85 ± 0.09 vs. 0.25 ± 0.08, < 0.01, withdrawal latency at 4 h (s) 8.5 ± 0.5 vs. 5.7 ± 1.4, < 0.05]. Low-dose amiodarone did not affect zymosan-induced paw inflammation. Local amiodarone did not cause cardiovascular or central nervous system side effects. Amiodarone may have the potential to be a long-acting and nociceptor-selective local anesthetic and analgesic method acting over open-state large-pore channels.

Chronic inflammation in the urinary bladder is a potential risk factor for bladder dysfunction, including interstitial cystitis/bladder pain syndrome (IC/BPS). Although several studies have reported that activation of transient receptor potential vanilloid 4 (TRPV4) contributes to bladder pain and overactive bladder with a cardinal symptom of acute or chronic cystitis, others have reported its involvement in the protective response mediated by lipopolysaccharides (LPS) to secrete anti-inflammatory/pro-resolution cytokines. Therefore, we investigated the potential benefit of an intravesical TRPV4 agonist for painful bladder hypersensitivity in a rat model of LPS-induced cystitis and determined whether its effects modulate the LPS signal for inflammatory reaction, cytokine release, and macrophage phenotype change. Previously, we showed that repeated intravesical instillations of LPS induce long-lasting bladder inflammation, pain, and overactivity in rats. In the present study, concurrent instillation of the selective TRPV4 agonist GSK1016790A (GSK) with LPS into the rat bladder improved LPS-induced bladder inflammation and reduced the number of mast cells. Furthermore, co-instillation of GSK prevented an increase in bladder pain-related behavior and voiding frequency caused by LPS. Cytokine profiling showed that LPS-stimulated inflammatory events, such as the production and secretion of pro-inflammatory cytokines (CXCL1, CXCL5, CXCL9, CXCL10, CCL3, CCL5, CCL20, and CX3CL1), are suppressed by GSK. Furthermore, TRPV4 activation switched LPS-stimulated pro-inflammatory M1-type macrophages to anti-inflammatory M2-type macrophages. These results suggest that TRPV4 activation in the bladder negatively regulates the pro-inflammatory response induced by LPS and prevents bladder hypersensitivity. These TRPV4 functions may be promising therapeutic targets for refractory IC/BPS.