Neuroimmune Pharmacology

An accumulating body of evidence suggests that endocannabinoids and cannabinoid receptors type 1 and 2 (CB(1), CB(2)) play a significant role in physiologic and pathologic processes, including cognitive and immune functions. While the addictive properties of marijuana, an extract from the Cannabis plant, are well recognized, there is growing appreciation of the therapeutic potential of cannabinoids in multiple pathologic conditions involving chronic inflammation (inflammatory bowel disease, arthritis, autoimmune disorders, multiple sclerosis, HIV-1 infection, stroke, Alzheimer's disease to name a few), mainly mediated by CB(2) activation. Development of CB(2) agonists as therapeutic agents has been hampered by the complexity of their intracellular signaling, relative paucity of highly selective compounds and insufficient data regarding end effects in the target cells and organs. This review attempts to summarize recent advances in studies of CB(2) activation in the setting of ne...

There is extensive bi-directional communication between the brain and the immune system in both health and disease. In recent years, the role of an altered immune system in the etiology of major psychiatric disorders has become more apparent. Studies have demonstrated that some patients with major psychiatric disorders exhibit characteristic signs of immune dysregulation and that this may be a common pathophysiological mechanism that underlies the development and progression of these disorders. Furthermore, many psychiatric disorders are also often accompanied by chronic medical conditions related to immune dysfunction such as autoimmune diseases, diabetes and atherosclerosis. One of the major psychiatric disorders that has been associated with an altered immune system is schizophrenia, with approximately one third of patients with this disorder showing immunological abnormalities such as an altered cytokine profile in serum and cerebrospinal fluid. An altered cytokine profile is also found in a proportion of patients with major depressive disorder and is thought to be potentially related to the pathophysiology of this disorder. Emerging evidence suggests that altered immune parameters may also be implicated in the neurobiological etiology of autism spectrum disorders. Further support for a role of immune dysregulation in the pathophysiology of these psychiatric disorders comes from studies showing the immunomodulating effects of antipsychotics and antidepressants, and the mood altering effects of anti-inflammatory therapies. This review will not attempt to discuss all of the psychiatric disorders that have been associated with an augmented immune system, but will instead focus on several key disorders where dysregulation of this system has been implicated in their pathophysiology including depression, schizophrenia and autism spectrum disorder.

Multiple sclerosis (MS) is the major immune-mediated, demyelinating, neurodegenerative disease of the central nervous system. Compounds within cannabis, notably Δ9-tetrahydrocannabinol (Δ9-THC) can limit the inappropriate neurotransmissions that cause MS-related problems and medicinal cannabis is now licenced for the treatment of MS symptoms. However, the biology indicates that the endocannabinoid system may offer the potential to control other aspects of disease. Although there is limited evidence that the cannabinoids from cannabis are having significant immunosuppressive activities that will influence relapsing autoimmunity, we and others can experimentally demonstrate that they may limit neurodegeneration that drives progressive disability. Here we show that synthetic cannabidiol can slow down the accumulation of disability from the inflammatory penumbra during relapsing experimental autoimmune encephalomyelitis (EAE) in ABH mice, possibly via blockade of voltage-gated sodium ch...

Methamphetamine (METH) is a widely abused drug. However, little is known about the effects of chronic METH consumption on HPA axis function and psychiatric symptomatology in adolescent METH users. The current study evaluated psychiatric symptoms and changes in the stress response of adolescent METH users. Forty-one adolescent METH users and 75 comparison subjects in the same age range (ages 12-23 years) were recruited. Each subject completed the Symptom Checklist-90R (SCL-90) and was evaluated using the Brief Psychiatric Rating Scale. In addition, the subjects completed the Trier Social Stress Test (TSST) and had salivary cortisol levels measured 30 min before, immediately after, and 60 min after the TSST. Adolescent METH users showed greater severity of symptoms across all measures of the SCL-90. Younger female METH users had the most symptoms. Furthermore, the METH users exhibited significantly enhanced cortisol levels immediately following the TSST (+31%, p = 0.03). Adolescent METH use is associated with greater psychiatric symptoms and enhanced cortisol secretion following a social stressor, particularly in younger female METH users. The psychiatric symptoms may reflect altered prefrontal cortical function resulting from chronic stress/drug use and the resulting glucocorticoid exposure. The results further suggest that treatment approaches should focus on stress-coping strategies to decrease the probability of relapse.

AbstractBruton’s tyrosine kinase (BTK), a critical component of B cell receptor signaling, has recently been implicated in regulation of the peripheral innate immune response. However, the role of BTK in microglia, the resident innate immune cells of the central nervous system, and its involvement in the pathobiology of neurodegenerative disease has not been explored. Here we found that BTK is a key regulator of microglial phagocytosis. Using potent BTK inhibitors and small interfering RNA (siRNA) against BTK, we observed that blockade of BTK activity decreased activation of phospholipase gamma 2, a recently identified genetic risk factor in Alzheimer’s disease (AD), and reduced phagocytosis in rodent microglia and human monocyte-derived macrophages. Inhibition of BTK signaling also decreased microglial uptake of synaptosomes but did not have major impacts on other key microglial functions such as migration and cytokine release. Similarly, blocking BTK function ex vivo in acute brai...

Smartphone-based interventions are increasingly used to support self-monitoring, self-management, and treatment and medication compliance in order to improve overall functioning and well-being. In attempting to develop a smartphone application (S-Health) that assists heroin-dependent patients in recovery, a series of focus groups (72 patients, 22 providers) were conducted in China, Taiwan, and the USA to obtain their perspectives on its acceptance and potential adoption. Data were analyzed according to the Diffusion of Innovation (DOI) theory of characteristics important to the adoption of innovation. Important to Relative Advantage, USA participants cited S-Health's potential ability to overcome logistical barriers, while those in China and Taiwan valued its potential to supplement currently limited services. In terms of Compatibility, participants across sites reported recovery needs and goals that such an application could be helpful in supporting; however, its utility during...

Despite the advent of antiretroviral therapy, complications of HIV-1 infection with concurrent drug abuse are an emerging problem. Opiates are well known to modulate immune responses by preventing the development of cell-mediated immune responses. Their effect on the pathogenesis of HIV-1 infection however remains controversial. Using the simian immunodeficiency virus/macaque model of HIV pathogenesis, we sought to explore the impact of morphine on disease progression and pathogenesis. Sixteen rhesus macaques were divided into two groups; four were administered saline and 12 others morphine routinely. Both groups of animals were then inoculated with SIVmacR71/17E and followed longitudinally for disease pathogenesis. The morphine group (M+V) exhibited a trend towards higher mortality rates and retardation in weight gain compared to the virus-alone group. Interestingly, a subset of M+V animals succumbed to disease within weeks post-infection. These rapid progressors also exhibited a h...

There are currently no consistent objective biochemical markers of alcohol abuse and alcoholism. Development of reliable diagnostic biomarkers that permit accurate assessment of alcohol intake and patterns of drinking is of prime importance to treatment and research fields. Diagnostic biomarker development in other diseases has demonstrated the utility of both open, systems biology, screening for biomarkers and more rational focused efforts on specific biomolecules or families of biomolecules. Long-term alcohol consumption leads to altered inflammatory cell and adaptive immune responses with associated pathologies and increased incidence of infections. This has led researchers to focus attention on identifying cytokine biomarkers in models of alcohol abuse. Alcohol is known to alter cytokine levels in plasma and a variety of tissues including lung, liver, and very importantly brain. A number of cytokine biomarker candidates have been identified, including: tumor necrosis factor-alph...

Neuroinflammation is a local tissue response to injurious stimuli in the central nervous system (CNS) and is characterized by glial reactivity, induction of cytokines and chemokines, and vascular permeability. The cytokine interleukin (IL)-1β is rapidly induced following CNS insult, and is chronically expressed in neurodegenerative disorders such as Alzheimer's disease (AD). We recently developed a novel method of sustained IL-1β production in the brain to study the link between IL-1β and AD pathogenesis. Utilizing this model, we have previously demonstrated reduction of plaque size and frequency accompanied by a robust neuroinflammatory response. These observations were limited to a single early time point in the course of AD plaque deposition and did not investigate other neurodegenerative endpoints. To extend these observations to other stages of disease progression and evaluate additional pathologic markers, we investigated the effects of age and duration of IL-1β overexpres...

Endogenous neuropeptide orphanin FQ/nociceptin (OFQ/N) and its receptor, nociceptin orphanin FQ peptide receptor (NOPr), play a modulatory role throughout the body including nociceptive sensitivity, motor function, spatial learning, and the immune system. NOPr is an inhibitory G protein coupled receptor (GPCR) that modulates expression and release of inflammatory mediators from immune cells and in the CNS. Inhibitory GPCRs have been shown to activate the immune and central nervous system regulator, nuclear factor kappa B (NFκB), whose family consists of several subunits. When activated, NFκB translocates to the nucleus and can modify transcription. To determine if OFQ/N modulates NFκB activity, SH-SY5Y human neuroblastoma cells were treated with OFQ/N and assessed for changes in nuclear accumulation, DNA binding, and transcriptional activation. For the first time, we show that OFQ/N increases the nuclear accumulation (1.9–2.8-fold) and the DNA binding of NFκB (2.9-fold) by 2 h as determined by immunoblotting and electromobility shift assay, respectively. OFQ/N induction of NFκB binding to DNA is protein kinase C-dependent and NOPr-specific. OFQ/N stimulated binding of both NFκB p50 and p65 subunits to their consensus binding site on DNA. OFQ/N also induces transcriptional activation of an NFκB reporter gene 2.2-fold by 2 h with an EC50 of 6.3 nM. This activation of NFκB by OFQ/N suggests a likely mechanism for its modulation of the central nervous and immune systems.

Marijuana cannabinoids, the endocannabinoids, and cannabinoid cell receptors have been shown to play important roles in immune regulation particularly as potent modulators of anti-inflammatory cytokines. The predominant cannabinoid receptor involved in this immune regulation is cannabinoid receptor 2 (CB(2)), which is predominantly expressed in B lymphocytes. However, the promoter region and mechanisms of CB(2) gene regulation are unknown in this immune cell type. Utilizing a combination of bioinformatics, 5' rapid amplification of cDNA ends (5' RACE), real-time reverse transcription-polymerase chain reaction, DNA sequencing, and luciferase reporter assays, we show that human B cells express one CB(2) transcript while mouse B cells express three CB(2) transcripts, with specific transcript selection occurring during B cell activation by lipopolysaccharide. Alignment of our sequenced RACE products to either the mouse or human genome, along with the GenBank submitted mRNA seque...

Injury to the peripheral nerve is traditionally referred to acquired nerve injury as they are the result of physical trauma due to laceration, stretch, crush and compression of nerves. However, peripheral nerve injury may not be completely limited to acquired physical trauma. Peripheral nerve injury equally implies clinical conditions like Guillain-Barré syndrome (GBS), Carpal tunnel syndrome, rheumatoid arthritis and diabetes. Physical trauma is commonly mono-neuropathic as it engages a single nerve and produces focal damage, while in the context of pathological conditions the damage is divergent involving a group of the nerve causing polyneuropathy. Damage to the peripheral nerve can cause a diverse range of manifestations from sensory impairment to loss of function with unpredictable recovery patterns. Presently no treatment option provides complete or functional recovery in nerve injury, as nerve cells are highly differentiated and inert to regeneration. However, the regenerativ...

Misfolding and aggregation of the amyloid β-protein (Aβ) are hallmarks of Alzheimer's disease. Both processes are dependent on the environmental conditions, including the presence of divalent cations, such as Cu(2+). Cu(2+) cations regulate early stages of Aβ aggregation, but the molecular mechanism of Cu(2+) regulation is unknown. In this study we applied single molecule AFM force spectroscopy to elucidate the role of Cu(2+) cations on interpeptide interactions. By immobilizing one of two interacting Aβ42 molecules on a mica surface and tethering the counterpart molecule onto the tip, we were able to probe the interpeptide interactions in the presence and absence of Cu(2+) cations at pH 7.4, 6.8, 6.0, 5.0, and 4.0. The results show that the presence of Cu(2+) cations change the pattern of Aβ interactions for pH values between pH 7.4 and pH 5.0. Under these conditions, Cu(2+) cations induce Aβ42 peptide structural changes resulting in N-termini interactions within the dimers. Cu...

This study highlights a novel approach to upregulate mitochondrial biogenesis in neuronal cells. RNS60 is a 0.9% saline solution containing oxygenated nanobubbles that is generated by subjecting normal saline to Taylor-Couette-Poiseuille (TCP) flow under elevated oxygen pressure. RNS60, but not NS (normal saline), PNS60 (saline containing a comparable level of oxygen without the TCP modification), or RNS10.3 (TCP-modified normal saline without excess oxygen), increased the expression of Nrf1, Tfam, Mcu, and Tom20 (genes associated with mitochondrial biogenesis) and upregulated mitochondrial biogenesis in MN9D dopaminergic neuronal cells. Similarly RNS60 also increased mitochondrial biogenesis in primary dopaminergic neurons and in the nigra of MPTP-intoxicated mice. However, RNS60 had no effect on lysosomal biogenesis. Interestingly, we found that RNS60 upregulated PGC1α and siRNA knockdown of PGC1α abrogated the ability of RNS60 to increase mitochondrial biogenesis. Furthermore, we...

Advances in the last several years have enhanced mechanistic understanding of Nef-induced CD4 and MHCI downregulation and have suggested a new paradigm for analyzing Nef function. In both of these cases, Nef acts by forming ternary complexes with significant contributions to stability imparted by non-canonical interactions. The mutational analyses and binding assays that have led to these conclusions are discussed. The recent progress has been dependent on conservative mutations and multi-protein binding assays. The poorly understood Nef functions of p21 activated protein kinase (PAK2) activation, enhancement of virion infectivity, and inhibition of immunoglobulin class switching are also likely to involve ternary complexes and non-canonical interactions. Hence, investigation of these latter Nef functions should benefit from a similar approach. Six historically used alanine substitutions for determining structure-function relationships of Nef are discussed. These are M20A, E62A/E63A...