Current Neuropharmacology - Volume 15, Issue 6, 2017

Background: Cannabis is the most widely used illicit drug in the world and there is growing concern about the mental health effects of cannabis use. These concerns are at least partly due to the strong increase in recreational and medical cannabis use and the rise in tetrahydrocannabinol (THC) levels. Cannabis is widely used to self-medicate by older people and people with brain disorders such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), bipolar disorder, and schizophrenia. Objective: This review provides an overview of the perceived benefits and adverse mental health effects of cannabis use in people with ALS, MS, AD, PD, bipolar disorder, and schizophrenia. Results: The reviewed studies indicate that cannabis use diminishes some symptoms associated with these disorders. Cannabis use decreases pain and spasticity in people with MS, decreases tremor, rigidity, and pain in people with PD, and improves the quality of life of ALS patients by improving appetite, and decreasing pain and spasticity. Cannabis use is more common among people with schizophrenia than healthy controls. Cannabis use is a risk factor for schizophrenia which increases positive symptoms in schizophrenia patients and diminishes negative symptoms. Cannabis use worsens bipolar disorder and there is no evidence that bipolar patients derive any benefit from cannabis. In late stage Alzheimer's patients, cannabis products may improve food intake, sleep quality, and diminish agitation. Conclusion: Cannabis use diminishes some of the adverse effects of neurological and psychiatric disorders. However, chronic cannabis use may lead to cognitive impairments and dependence.

Background: Understanding the complexities associated with the ischemic condition and identifying therapeutic targets in ischemia is a continued challenge in stroke biology. Emerging evidence reveals the potential involvement of epigenetic mechanisms in the incident and outcome of stroke, suggesting novel therapeutic options of targeting different molecules related to epigenetic regulation. Objective: This review summarizes our current understanding of ischemic pathophysiology, describes various in vivo and in vitro models of ischemia, and examines epigenetic modifications associated with the ischemic condition. Method: We focus on microRNAs, DNA methylation, and histone modifying enzymes, and present how epigenetic studies are revealing novel drug target candidates in stroke. Conclusion: Finally, we discuss emerging approaches for the prevention and treatment of stroke and post-stroke effects using pharmacological interventions with a wide therapeutic window.

Background: Posttraumatic stress disorder (PTSD) is a severe problem among soldiers with combating experience difficult to treat. The pathogenesis is still not fully understood at the psychological level. Therefore, genetic research became a focus of interest. The identification of single nucleotide polymorphisms (SNPs) may help to predict, which persons are at high risk to develop PTSD as a starting point to develop novel targeted drugs for treatment. Methods: We conducted a systematic review on SNPs in genes related to PTSD pathology and development of targeted pharmacological treatment options based on PubMed database searches. We focused on clinical trials with military personnel. Results: SNPs in 22 human genes have been linked to PTSD. These genes encode proteins acting as neurotransmitters and receptors, downstream signal transducers and metabolizing enzymes. Pharmacological inhibitors may serve as drug candidates for PTSD treatment, e.g. β2 adrenoreceptor antagonists, dopamine antagonists, partial dopamine D2 receptor agonists, dopamine β hydroxylase inhibitors, fatty acid amid hydrolase antagonists, glucocorticoid receptor agonists, tropomyosin receptor kinase B agonists, selective serotonin reuptake inhibitors, catechol-O-methyltransferase inhibitors, gamma-amino butyric acid receptor agonists, glutamate receptor inhibitors, monoaminoxidase B inhibitors, N-methyl-d-aspartate receptor antagonists. Conclusion: The combination of genetic and pharmacological research may lead to novel targetbased drug developments with improved specificity and efficacy to treat PTSD. Specific SNPs may be identified as reliable biomarkers to assess individual disease risk. Focusing on soldiers suffering from PTSD will not only help to improve treatment options for this specific group, but for all PTSD patients and the general population.

Background: Traumatic optic nerve injury is a leading cause of irreversible blindness across the world and causes progressive visual impairment attributed to the dysfunction and death of retinal ganglion cells (RGCs). To date, neither pharmacological nor surgical interventions are sufficient to halt or reverse the progress of visual loss. Axon regeneration is critical for functional recovery of vision following optic nerve injury. After optic nerve injury, RGC axons usually fail to regrow and die, leading to the death of the RGCs and subsequently inducing the functional loss of vision. However, the detailed molecular mechanisms underlying axon regeneration after optic nerve injury remain poorly understood. Methods: Research content related to the detailed molecular mechanisms underlying axon regeneration after optic nerve injury have been reviewed. Results: The present review provides an overview of regarding potential strategies for axonal regeneration of RGCs and optic nerve repair, focusing on the role of cytokines and their downstream signaling pathways involved in intrinsic growth program and the inhibitory environment together with axon guidance cues for correct axon guidance. A more complete understanding of the factors limiting axonal regeneration will provide a rational basis, which contributes to develop improved treatments for optic nerve regeneration. These findings are encouraging and open the possibility that clinically meaningful regeneration may become achievable in the future. Conclusion: Combination of treatments towards overcoming growth-inhibitory molecules and enhancing intrinsic growth capacity combined with correct guidance using axon guidance cues is crucial for developing promising therapies to promote axon regeneration and functional recovery after ON injury.

Background: Immunosuppressive drugs have been used in the treatment of multiple sclerosis (MS) for a long time. Today, orally available second generation immunosuppressive agents have been approved or are filed for licensing as MS therapeutics. Due to semi-selective targeting of cellular processes, these second-generation immunosuppressive compounds might rather be immunomodulatory. For example, Teriflunomide inhibits the de novo pyrimidine synthesis and thus only targets rapidly proliferating cells, including lymphocytes. It is used as first line disease modifying therapy (DMT) in relapsing-remitting MS (RRMS). Methods: Review of online content related to oral immunosuppressants in MS with an emphasis on Teriflunomide. Results: Teriflunomide and Cladribine are second-generation immunosuppressants that are efficient in the treatment of MS patients. For Teriflunomide, a daily dose of 14 mg reduces the annualized relapse rate (ARR) by more than 30% and disability progression by 30% compared to placebo. Cladribine reduces the ARR by about 50% compared to placebo but has not yet been licensed due to unresolved safety concerns. We also discuss the significance of older immunosuppressive compounds including Azathioprine, Mycophenolate mofetile, and Cyclophosphamide in current MS therapy. Conclusion: Teriflunomide has shown a favorable safety and efficacy profile in RRMS and is a therapeutic option for a distinct group of adult patients with RRMS.

Background: Every year, strokes take millions of lives and leave millions of individuals living with permanent disabilities. Recently more researchers embrace the concept of the neurovascular unit (NVU), which encompasses neurons, endothelial cells (ECs), pericytes, astrocyte, microglia, and the extracellular matrix. It has been well-documented that NVU emerged as a new paradigm for the exploration of mechanisms and therapies in ischemic stroke. To better understand the complex NVU and broaden therapeutic targets, we must probe the roles of multiple cell types in ischemic stroke. The aims of this paper are to introduce the biological characteristics of brain pericytes and the available evidence on the diverse functions and mechanisms involving the pericytes in the context of ischemic stroke. Methods: Research and online content related to the biological characteristics and pathophysiological roles of pericytes is review. The new research direction on the Pericytes in ischemic stroke, and the potential therapeutic targets are provided. Results: During the different stages of ischemic stroke, pericytes play different roles: 1) On the hyperacute phase of stroke, pericytes constriction and death may be a cause of the no-reflow phenomenon in brain capillaries; 2) During the acute phase, pericytes detach from microvessels and participate in inflammatory-immunological response, resulting in the BBB damage and brain edema. Pericytes also provide benefit for neuroprotection by protecting endothelium, stabilizing BBB and releasing neurotrophins; 3) Similarly, during the later recovery phase of stroke, pericytes also contribute to angiogenesis, neurogenesis, and thereby promote neurological recovery. Conclusion: This emphasis on the NVU concept has shifted the focus of ischemic stroke research from neuro-centric views to the complex interactions within NVU. With this new perspective, pericytes that are centrally positioned in the NVU have been widely studied in ischemic stroke. More work is needed to elucidate the beneficial and detrimental roles of brain pericytes in ischemic stroke that may serve as a basis for potential therapeutic targets.

Background: Growing body of evidence suggests that the pathogenesis of Alzheimer's disease (AD), a progressing neurodegenerative condition, is not limited to the neuronal compartment, but also involves various immunological mechanisms. Insoluble Aβ aggregates in the brain can induce the activation of microglia, resulting in the synthesis of proinflammatory mediators, which further can stimulate astrocytic expression of YKL-40. Therefore, the aim of the current review is to present up-to-date data about the role of YKL-40 as a biomarker of AD as well as the possibility of therapeutic strategies targeting neuroinflammation. Objective/Methods: We searched PubMed articles for the terms “YKL-40”, “neurodegeneration”, “neuroinflammation” and “Alzheimer's disease”, and included papers focusing on this review's scope. Results: Recent studies indicate that CSF concentrations of YKL-40 were significantly higher in AD patients than in cognitively normal individuals and correlated with dementia biomarkers, such as tau proteins and amyloid beta. Determination of YKL-40 CSF concentration may be also helpful in differentiation between types of dementia and in the distinction of patients in the stable phase of MCI from those who progressed to dementia. Moreover, significantly increased levels of YKL-40 mRNA were found in AD brains in comparison with non-demented controls. Additionally, it was suggested that anti-inflammatory treatment might relief the symptoms of AD and slow its progression. Conclusion: Based on the recent knowledge, YKL-40 might be useful as a possible biomarker in the diagnosis and prognosis of AD. Modulation of risk factors and targeting of immune mechanisms, including systemic inflammation could lead to future preventive or therapeutic strategies for AD.

Background: Spike-wave discharges, underlying absence seizures, are generated within a cortico-thalamo-cortical network that involves the somatosensory cortex, the reticular thalamic nucleus, and the ventrobasal thalamic nuclei. Activation of T-type voltage-sensitive calcium channels (VSCCs) contributes to the pathological oscillatory activity of this network, and some of the first-line drugs used in the treatment of absence epilepsy inhibit T-type calcium channels. The α2δ subunit is a component of high voltage-activated VSCCs (i.e., L-, N-, P/Q-, and R channels) and studies carried out in heterologous expression systems suggest that it may also associate with T channels. The α2δ subunit is also targeted by thrombospondins, which regulate synaptogenesis in the central nervous system. Objective: To discuss the potential role for the thrombospondin/α2δ axis in the pathophysiology of absence epilepsy. Methods: We searched PubMed articles for the terms “absence epilepsy”, “T-type voltage-sensitive calcium channels”, “α2δ subunit”, “ducky mice”, “pregabalin”, “gabapentin”, “thrombospondins”, and included papers focusing this Review's scope. Results: We moved from the evidence that mice lacking the α2δ-2 subunit show absence seizures and α 2δ ligands (gabapentin and pregabalin) are detrimental in the treatment of absence epilepsy. This suggests that α2δ may be protective against absence epilepsy via a mechanism that does not involve T channels. We discuss the interaction between thrombospondins and α2δ and its potential relevance in the regulation of excitatory synaptic formation in the cortico-thalamo-cortical network. Conclusion: We speculate on the possibility that the thrombospondin/α2 δ axis is critical for the correct functioning of the cortico-thalamo-cortical network, and that abnormalities in this axis may play a role in the pathophysiology of absence epilepsy.

Since its discovery in 1984, the beta amyloid peptide has treaded the boards of neurosciences as the star molecule in Alzheimer's disease pathogenesis. In the last decade, however, this vision has been challenged by evidence-based medicine showing the almost complete failure of clinical trials that experimented anti-amyloid therapies with great hopes. Moreover, data have accumulated which clearly indicate that this small peptide plays a key role in the physiological processes of memory formation. In the present review, we will discuss the different aspects of the amyloid cascade hypothesis, highlighting its pros and cons, and we will analyse the results of the therapeutic approaches attempted to date that should change the direction of Alzheimer's disease research in the future.