Posted by Kostas Pantremenos in Pharmacological, TBI on December 20, 2019
The endogenous cannabinoid (endocannabinoid) system regulates a diverse array of physiological processes and unsurprisingly possesses considerable potential targets for the potential treatment of numerous disease states, including two receptors (i.e., CB1 and CB2 receptors) and enzymes regulating their endogenous ligands N-arachidonoylethanolamine (anandamide) and 2-arachidonyl glycerol (2-AG). Increases in brain levels of endocannabinoids to pathogenic events suggest this system plays a role in compensatory repair mechanisms. Traumatic brain injury (TBI) pathology remains mostly refractory to currently available drugs, perhaps due to its heterogeneous nature in etiology, clinical presentation, and severity. Here, we review pre-clinical studies assessing the therapeutic potential of cannabinoids and manipulations of the endocannabinoid system to ameliorate TBI pathology. Specifically, manipulations of endocannabinoid degradative enzymes (e.g., fatty acid amide hydrolase, monoacylglycerol lipase, and α/β-hydrolase domain-6), CB1 and CB2 receptors, and their endogenous ligands have shown promise in modulating cellular and molecular hallmarks of TBI pathology such as; cell death, excitotoxicity, neuroinflammation, cerebrovascular breakdown, and cell structure and remodeling. TBI-induced behavioral deficits, such as learning and memory, neurological motor impairments, post-traumatic convulsions or seizures, and anxiety also respond to manipulations of the endocannabinoid system. As such, the endocannabinoid system possesses potential drugable receptor and enzyme targets for the treatment of diverse TBI pathology. Yet, full characterization of TBI-induced changes in endocannabinoid ligands, enzymes, and receptor populations will be important to understand that role this system plays in TBI pathology. Promising classes of compounds, such as the plant-derived phytocannabinoids, synthetic cannabinoids, and endocannabinoids, as well as their non-cannabinoid receptor targets, such as TRPV1 receptors, represent important areas of basic research and potential therapeutic interest to treat TBI.
Traumatic brain injury accounts for approximately 10 million deaths and/or hospitalizations annually in the world, and approximately 1.5 million annual emergency room visits and hospitalizations in the US (Langlois et al., 2006). Young men are consistently over-represented as being at greatest risk for TBI (Langlois et al., 2006). While half of all traumatic deaths in the USA are due to brain injury (Mayer and Badjatia, 2010), the majority of head injuries are considered mild and often never receive medical treatment (Corrigan et al., 2010). Survivors of TBI are at risk for lowered life expectancy, dying at a 3⋅2 times more rapid rate than the general population (Baguley et al., 2012). Survivors also face long term physical, cognitive, and psychological disorders that greatly diminish quality of life. Even so-called mild TBI without notable cell death may lead to enduring cognitive deficits (Niogi et al., 2008; Rubovitch et al., 2011). A 2007 study estimated that TBI results in $330,827 of average lifetime costs associated with disability and lost productivity, and greatly outweighs the $65,504 estimated costs for initial medical care and rehabilitation (Faul et al., 2007), demonstrating both the long term financial and human toll of TBI.
The development of management protocols in major trauma centers (Brain Trauma Foundation et al., 2007) has improved mortality and functional outcomes (Stein et al., 2010). Monitoring of intracranial pressure is now standard practice (Bratton et al., 2007), and advanced MRI technologies help define the extent of brain injury in some cases (Shah et al., 2012). Current treatment of major TBI is primarily managed through surgical intervention by decompressive craniotomy (Bullock et al., 2006) which involves the removal of skull segments to reduce intracranial pressure. Delayed decompressive craniotomy is also increasingly used for intractable intracranial hypertension (Sahuquillo and Arikan, 2006). The craniotomy procedure is associated with considerable complications, such as hematoma, subdural hygroma, and hydrocephalus (Stiver, 2009). At present, the pathology associated with TBI remains refractive to currently available pharmacotherapies (Meyer et al., 2010) and as such represents an area of great research interest and in need of new potential targets. Effective TBI drug therapies have yet to be proven, despite promising preclinical data (Lu et al., 2007; Mbye et al., 2009; Sen and Gulati, 2010) plagued by translational problems once reaching clinical trials (Temkin et al., 2007; Tapia-Perez et al., 2008; Mazzeo et al., 2009).
The many biochemical events that occur in the hours and months following TBI have yielded preclinical studies directed toward a single injury mechanism. However, an underlying premise of the present review is an important need to address the multiple targets associated with secondary injury cascades following TBI. A growing body of published scientific research indicates that the endogenous cannabinoid (endocannabinoid; eCB) system possesses several targets uniquely positioned to modulate several key secondary events associated with TBI. Here, we review the preclinical work examining the roles that the different components of the eCB system play in ameliorating pathologies associated with TBI.
Originally, “Cannabinoid” was the collective name assigned to the set of naturally occurring aromatic hydrocarbon compounds in the Cannabis sativa plant (Mechoulam and Goani, 1967). Cannabinoid now more generally refers to a much more broad set of chemicals of diverse structure whose pharmacological actions or structure closely mimic that of plant-derived cannabinoids. Three predominant categories are currently in use; plant-derived phytocannabinoids (reviewed in Gertsch et al., 2010), synthetically produced cannabinoids used as research (Wiley et al., 2014) or recreational drugs (Mills et al., 2015), and the endogenous cannabinoids, N-arachidonoylethanolamine (anandamide) (Devane et al., 1992) and 2-AG (Mechoulam et al., 1995; Sugiura et al., 1995).
These three broad categories of cannabinoids generally act through cannabinoid receptors, two types of which have so far been identified, CB1 (Devane et al., 1988) and CB2 (Munro et al., 1993). Both CB1 and CB2 receptors are coupled to signaling cascades predominantly through Gi/o-coupled proteins. CB1 receptors mediate most of the psychomimetic effects of cannabis, its chief psychoactive constituent THC, and many other CNS active cannabinoids. These receptors are predominantly expressed on pre-synaptic axon terminals (Alger and Kim, 2011), are activated by endogenous cannabinoids that function as retrograde messengers, which are released from post-synaptic cells, and their activation ultimately dampens pre-synaptic neurotransmitter release (Mackie, 2006). Acting as a neuromodulatory network, the outcome of cannabinoid receptor signaling depends on cell type and location. CB1 receptors are highly expressed on neurons in the central nervous system (CNS) in areas such as cerebral cortex, hippocampus, caudate-putamen (Herkenham et al., 1991). In contrast, CB2 receptors are predominantly expressed on immune cells, microglia in the CNS, and macrophages, monocytes, CD4+ and CD8+ T cells, and B cells in the periphery (Cabral et al., 2008). Additionally, CB2 receptors are expressed on neurons, but to a much less extent than CB1 receptors (Atwood and MacKie, 2010). The abundant, yet heterogeneous, distribution of CB1 and CB2 receptors throughout the brain and periphery likely accounts for their ability to impact a wide variety of physiological and psychological processes (e.g., memory, anxiety, and pain perception, reviewed in Di Marzo, 2008) many of which are impacted following TBI.
Another unique property of the eCB system is the functional selectivity produced by its endogenous ligands. Traditional neurotransmitter systems elicit differential activation of signaling pathways through activation of receptor subtypes by one neurotransmitter (Siegel, 1999). However, it is the endogenous ligands of eCB receptors which produce such signaling specificity. Although several endogenous cannabinoids have been described (Porter et al., 2002; Chu et al., 2003; Heimann et al., 2007) the two most studied are anandamide (Devane et al., 1992) and 2-AG (Mechoulam et al., 1995; Sugiura et al., 1995). 2-AG levels are three orders of magnitude higher than those of anandamide in brain (Béquet et al., 2007). Additionally, their receptor affinity (Pertwee and Ross, 2002; Reggio, 2002) and efficacy differ, with 2-AG acting as a high efficacy agonist at CB1 and CB2 receptors, while anandamide behaves as a partial agonist (Hillard, 2000a). In addition, anandamide binds and activates TRPV1 receptors (Melck et al., 1999; Zygmunt et al., 1999; Smart et al., 2000), whereas 2-AG also binds GABAA receptors (Sigel et al., 2011). As such, cannabinoid ligands differentially modulate similar physiological and pathological processes.
Distinct sets of enzymes, which regulate the biosynthesis and degradation of the eCBs and possess distinct anatomical distributions (see Figure Figure11), exert control over CB1 and CB2 receptor signaling. Inactivation of anandamide occurs predominantly through FAAH (Cravatt et al., 1996, 2001), localized to intracellular membranes of postsynaptic somata and dendrites (Gulyas et al., 2004), in areas such as the neocortex, cerebellar cortex, and hippocampus (Egertová et al., 1998). Inactivation of 2-AG proceeds primarily via MAGL (Dinh et al., 2002; Blankman et al., 2007), expressed on presynaptic axon terminals (Gulyas et al., 2004), and demonstrates highest expression in areas such as the thalamus, hippocampus, cortex, and cerebellum (Dinh et al., 2002). The availability of pharmacological inhibitors for eCB catabolic enzymes has allowed the selective amplification of anandamide and 2-AG levels following brain injury as a key strategy to enhance eCB signaling and to investigate their potential neuroprotective effects.
FIGURE 1
Endocannabinoid system cell localization by CNS cell type. Endocannabinoid functional specialization among CNS cell types is determined by the cellular compartmentalization of biosynthetic and catabolic enzymes (biosynthesis by NAPE and DAGL-α, -β, catabolism by FAAH and MAGL). Cellular level changes in eCB biosynthetic and catabolic enzymes as a result of brain injury have yet to be investigated, though morphological and molecular reactivity by cell type is well documented.
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Continue —-> Endocannabinoids: A Promising Impact for Traumatic Brain Injury
Posted by Kostas Pantremenos in Epilepsy on February 21, 2019
Epilepsy is a neurological disorder afflicting ~65 million people worldwide. It is caused by aberrant synchronized firing of populations of neurons primarily due to imbalance between excitatory and inhibitory neurotransmission. Hence, the historical focus of epilepsy research has been neurocentric. However, the past two decades have enjoyed an explosion of research into the role of glia in supporting and modulating neuronal activity, providing compelling evidence of glial involvement in the pathophysiology of epilepsy. The mechanisms by which glia, particularly astrocytes and microglia, may contribute to epilepsy and consequently could be harnessed therapeutically are discussed in this Review.
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via Neuron–glia interactions in the pathophysiology of epilepsy | Nature Reviews Neuroscience
Posted by Kostas Pantremenos in REHABILITATION on July 17, 2017
Advances in acute stroke treatment and the widespread establishment of dedicated stroke units have resulted in an increase in poststroke survival and life expectancy. However, stroke remains a leading cause of long-term disability worldwide, making the improvement of poststroke outcomes a chief healthcare goal for many countries. The current strategies strive to reduce the initial injury by acutely implementing thrombolytic and/or endovascular interventions, to better understand the major determinants that influence the stroke recovery and to search for innovative, effective and accessible recovery and rehabilitation modalities that can mitigate various poststroke deficits and enhance the quality of life. These approaches require a collaboration and integration of fundamental and clinical science research to more efficiently translate benchwork results into therapeutic bedside interventions. Due to a variety of stroke research advances in both the basic and clinical sciences over the last few years, especially in 2016, the field of stroke recovery and rehabilitation has celebrated many hopes and progresses. Our goal was to explore these studies and better identify, understand and integrate key findings for the purpose of identifying new targets that could be translated into clinically rewarding therapeutic interventions in future.
We manually searched professional journals with an average 5-year impact factor >3 (from 2012 to 2016) that were known to publish manuscript with topics in stroke recovery and rehabilitation. We aimed to selectively highlight relevant basic and clinical science stroke recovery research published between December 2015 and December 2016 in these journals. Certain selection biases cannot be completely ruled out and omissions are possible. The list of journals are Science, Nature, Nature Neuroscience, Neuron, Proceedings of the National Academy of Sciences of the United States of America, Neurobiology of Disease, Scientific Report, PLOS ONE, Acta Neuropathologica, Journal of Neuroscience, Annals of Neurology, Neurology, JAMA Neurology, Stroke, The Lancet, Lancet of Neurology, JAMA, Brain, Brain Stimulation, Stem Cells, Cell Death and Differentiation, Neurorehabilitation and Neural Repair, Journal of Cerebral Blood Flow and Metabolism and New England Journal of Medicine.
Figure 1 (A) Shows the number of manuscripts from 2007 to 2016 if searching Pubmed with term of ‘transcranial direct current stimulation (tDCS)’; (B) shows the changes of effect size (ie, Hedge’s g) of tDCS from poststroke upper extremity motor recovery trials over the years. The values of Hedge’s g are from the able 2 in Dr Chhatbar’s study.45
Posted by Kostas Pantremenos in Epilepsy, Pharmacological on December 4, 2016
The University of Utah College of Pharmacy’s Anticonvulsant Drug Development (ADD) Program has been awarded a five-year $19.5 million contract renewal with the National Institutes of Health (NIH) to test drugs to treat epilepsy, and the major focus of the project is to address needs that affect millions of people worldwide -identify novel investigational compounds to prevent the development of epilepsy or to treat refractory, or drug-resistant, epilepsy.
The ADD program began in 1975 and since then has tested the vast majority of drugs used to control seizures in patients with epilepsy, helping millions of people worldwide. Unfortunately, almost one-third of the estimated 50 million people with the disorder has refractory, or unresponsive, epilepsy that isn’t adequately controlled by medications currently available. The contract renewal, awarded through the National Institute of Neurological Disorders and Stroke (NINDS) to the U Department of Pharmacology and Toxicology, represents a shift in the mission to identify new therapies, according to ADD Director Karen S. Wilcox, Ph.D., professor and chair of pharmacology and toxicology and principal investigator of the contract.
“We’re proud that over the past 41 years, the ADD program has played a key role in identifying and characterizing many of the drugs now available to treat patients with epilepsy and to control their seizures,” Wilcox says. “Now, we’re looking for drugs that can modify or prevent the disease, particularly in those patients either with refractory epilepsy or at risk for developing epilepsy following a brain injury.”
Epilepsy is a group of neurological disorders characterized by a tendency for repeated seizures over time. It occurs when permanent changes in the brain result in abnormal or excessive neuronal activity in the brain. An estimated 2.9 million people in the United States and 50 million people worldwide have active epilepsy, according the Centers for Disease Control and World Health Organization. There is no cure for epilepsy and the mainstay of treatment is anti-seizure medications.
ADD is a long-standing program dedicated to testing drugs to treat epilepsy. It has received continuous funding from NINDS’ Epilepsy Therapy Screening Program (ETSP) (formerly known as the Anticonvulsant Screening Program) since its founding in 1974. In collaboration, the ETSP and the ADD Program have evaluated more than 32,000 compounds. ADD received the contract in a competitive bidding process. The renewal of the contractual relationship between the NINDS and the University of Utah reflects the ongoing commitment of the NIH and the ETSP to finding and developing novel therapies for epilepsy and represents a unique partnership between government, industry, and academia.
“The NIH-NINDS ETSP is pleased to continue the productive relationship with the University of Utah,” says Dr. John Kehne, a Program Director at NINDS and head of the ETSP. “These and other efforts supported by the NINDS will help to discover new pharmacotherapies to address the unmet medical needs of people living with epilepsy.”
In addition to its focus on evaluating potential candidate drugs for the treatment of therapy-resistant epilepsy, the mission of the ADD Program includes efforts to identify novel therapies for different types of epilepsy. The program also serves as a base for innovative basic research that sheds new light on the pathophysiology of epilepsy and provides a unique training environment for students, research fellows, and visiting scientists. Currently, the ADD program employ18 researchers, technicians, and staff. Cameron S. Metcalf, Ph.D is associate director and a co-Investigator of the contract and Peter J. West, Ph.D., and Misty D. Smith, Ph.D, research assistant professors of pharmacology and toxicology, are also co-investigators on the contract renewal.
Although there currently is no cure for epilepsy, Wilcox, who previously served as a co-Investigator of ADD before taking over as PI in 2016, believes that can be changed.
“The brain has remarkable plasticity throughout a person’s life,” she says. “If we learn enough about neuroscience and the details of how the brain works, it’s very possible to find a cure.”
Source: ADD Program receives $19.5 million NIH contract to test drugs for treating epilepsy
Posted by Kostas Pantremenos in Gait Rehabilitation - Foot Drop on November 16, 2015
Summary
We reviewed neural control and biomechanical description of gait in both non-disabled and post-stroke subjects. In addition, we reviewed most of the gait rehabilitation strategies currently in use or in development and observed their principles in relation to recent pathophysiology of post-stroke gait.
In both non-disabled and post-stroke subjects, motor control is organized on a task-oriented basis using a common set of a few muscle modules to simultaneously achieve body support, balance control, and forward progression during gait.
Hemiparesis following stroke is due to disruption of descending neural pathways, usually with no direct lesion of the brainstem and cerebellar structures involved in motor automatic processes. Post-stroke, improvements of motor activities including standing and locomotion are variable but are typically characterized by a common postural behaviour which involves the unaffected side more for body support and balance control, likely in response to initial muscle weakness of the affected side.
Various rehabilitation strategies are regularly used or in development, targeting muscle activity, postural and gait tasks, using more or less high-technology equipment. Reduced walking speed often improves with time and with various rehabilitation strategies, but asymmetric postural behaviour during standing and walking is often reinforced, maintained, or only transitorily decreased. This asymmetric compensatory postural behaviour appears to be robust, driven by support and balance tasks maintaining the predominant use of the unaffected side over the initially impaired affected side.
Based on these elements, stroke rehabilitation including affected muscle strengthening and often stretching would first need to correct the postural asymmetric pattern by exploiting postural automatic processes in various particular motor tasks secondarily beneficial to gait.
Source: Gait post-stroke: Pathophysiology and rehabilitation strategies
TBI Rehabilitation 