Amelioration of visual deficits and visual system pathology after mild TBI with the cannabinoid type-2 receptor inverse agonist SMM-189

Guley, Natalie; Mar, Nobel A. Del; Ragsdale, Tyler D.; Li, Chunyan; Perry, Aaron M.; Moore, Bob M.; Honig, Marcia G.; Reiner, Anton

doi:10.1016/j.exer.2019.03.013

Cited by 39 publications

(66 citation statements)

References 94 publications

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“…Another study examined the effects of SMM-189, a CB2R inverse agonist, on microglial phenotype in a TBI mouse model. Consistent with the in vitro study, CD16/32 + cells were decreased while CD206 + cells were increased by SMM-189 administration in the right optic tract 3 days after blast injury (106). Very recently, the same group showed that raloxifene, which is a CB2R inverse agonist (127) but also known as a selective estrogen receptor modulator (128), induced anti-inflammatory effects by modulating the M1/M2 microglial phenotype (105).…”

Section: Microglial Polarization By Ecb In Tbi Modelssupporting

confidence: 74%

Endocannabinoid Modulation of Microglial Phenotypes in Neuropathology

2020

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Microglia, the resident immune cells of the central nervous system, mediate brain homeostasis by controlling neuronal proliferation/differentiation and synaptic activity. In response to external signals from neuropathological conditions, homeostatic (M0) microglia can adopt one of two activation states: the classical (M1) activation state, which secretes mediators of the proinflammatory response, and the alternative (M2) activation state, which presumably mediates the resolution of neuroinflammation and tissue repair/remodeling. Since chronic inflammatory activation of microglia is correlated with several neurodegenerative diseases, functional modulation of microglial phenotypes has been considered as a potential therapeutic strategy. The endocannabinoid (eCB) system, composed of cannabinoid receptors and ligands and their metabolic/biosynthetic enzymes, has been shown to activate anti-inflammatory signaling pathways that modulate immune cell functions. Growing evidence has demonstrated that endogenous, synthetic, and plant-derived eCB agonists possess therapeutic effects on several neuropathologies; however, the molecular mechanisms that mediate the anti-inflammatory effects have not yet been identified. Over the last decade, it has been revealed that the eCB system modulates microglial activation and population. In this review, we thoroughly examine recent studies on microglial phenotype modulation by eCB in neuroinflammatory and neurodegenerative disease conditions. We hypothesize that cannabinoid 2 receptor (CB2R) signaling shifts the balance of expression between neuroinflammatory (M1-type) genes, neuroprotective (M2-type) genes, and homeostatic (M0-type) genes toward the latter two gene expressions, by which microglia acquire therapeutic functionality.

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Section: Microglial Polarization By Ecb In Tbi Modelssupporting

confidence: 74%

Endocannabinoid Modulation of Microglial Phenotypes in Neuropathology

2020

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“…This suggests that there are degenerating axons in the regions noted. Supporting evidence for similar axonal injury in the optic nerve has also been found in blast models [23, 33,34] and midline fluid percussion injury as well as targeted DIA to the optic nerve [47].…”

Section: Discussionsupporting

confidence: 61%

“…As we and others have previously shown that outcome differences between mice separated by as little as two weeks of age arise after mild TBI in memory performance, mortality, and severity of brain pathophysiology [26][27][28][29][30][31][32] it is, therefore, likely that these differences are also present across age groups in the visual system. Moreover, studies on optic nerve injury have only recently begun to analyze central projections of the optic nerve like the LGN [17,21,33,34], the SC [21,23], and the supra-oculomotor nucleus and caudate [21] but none have been conducted in an adolescent population.…”

Section: Introductionmentioning

confidence: 99%

Indirect traumatic optic neuropathy after head trauma in adolescent male mice is associated with behavioral visual impairment, neurodegeneration, and elevated endoplasmic reticulum stress markers at acute and subacute times

Cansler¹,

Guilhaume-Corrêa

Day³

et al. 2020

Preprint

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Traumatic brain injury (TBI) results in a number of impairments, often including visual symptoms. In some cases, visual symptoms after head trauma are mediated by traumatic injury to the optic nerve, termed traumatic optic neuropathy (TON), which has few options for treatment. Using a murine closed head model of head trauma, we have previously reported in adult mice that there is relatively selective injury to the optic system of the brain. In the current study, we performed blunt head trauma on adolescent C57BL/6 mice, and investigated visual impairment and retinal and optic system injury, using behavioral and histologic methods. After injury, mice display evidence of decreased optomotor responses, as evidence by decreased optokinetic nystagmus responses. There does not appear to be a significant change in circadian locomotor behavior patterns, although there is an overall decrease in locomotor behavior in mice with head injury. There is evidence of axonal degeneration of optic nerve fibers, with associated retinal ganglion cell death. There is also evidence of astrogliosis and microgliosis in major central targets of optic nerve projections. Further, there is elevated expression of markers of endoplasmic reticulum (ER) stress in retinas of injured mice. The current results extend our previous findings in adult mice into adolescent mice, provide direct evidence of retinal ganglion cell injury after head trauma, and suggest that axonal degeneration is associated with elevated ER stress in this model of TON. Visual impairment, histologic markers of gliosis and neurodegeneration, and elevated ER stress marker expression persist for at least 30 days after injury.

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“…Another very efficacious agent, at least for mouse TBI that has been studied in cell culture and animal models for almost 20 years now, is pifithrin [ 21 , 22 ]. Moreover, compounds acting on the cannabinoid type-2 (CB-2) receptor (including SMM-189, as well as raloxifene) can be very effective for treatment of TBI [ 1 , 23 , 24 , 25 , 26 ]. Finally, two other promising representatives of these five efficacious agent are ligands for the mitochondrial 18-kDa translocator protein (TSPO) and a brown seaweed product fucoidan, reviewed elsewhere [ 27 , 28 , 29 ].…”

Section: Raloxifene In the Context Of Other Advances In Treatmentsmentioning

confidence: 99%

“…Interestingly, for these beneficial raloxifene effects, interactions with the cannabinoid type-2 receptor (CB-2) were essential [ 1 ]. In other experiments, treatment with the CB-2 inverse agonist SMM-189 for 2 weeks after closed-head blast TBI greatly attenuated the visual deficits and retinal pathology otherwise produced in mice, including reduction of the deleterious role of microglia in the injury process after this trauma [ 23 , 24 , 25 , 26 , 119 ]. Thus, in general, the CB-2 receptor provides a robust pathway for healing of brain injury.…”

Section: Brain Diseases Brain Injuries and Underlying Functions mentioning

confidence: 99%

Raloxifene as Treatment for Various Types of Brain Injuries and Neurodegenerative Diseases: A Good Start

Veenman

2020

IJMS

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Recent studies have shown that the selective estrogen receptor modulator (SERM) raloxifene had pronounced protective effects against progressing brain damage after traumatic brain injury (TBI) in mice. These studies, indicating beneficial effects of raloxifene for brain health, prompted the study of the history and present state of knowledge of this topic. It appears that, apart from raloxifene, to date, four nonrelated compounds have shown comparable beneficial effects—fucoidan, pifithrin, SMM-189 (5-dihydroxy-phenyl]-phenyl-methanone), and translocator protein (TSPO) ligands. Raloxifene, however, is ahead of the field, as for more than two decades it has been used in medical practice for various chronic ailments in humans. Thus, apart from different types of animal and cell culture studies, it has also been assessed in various human clinical trials, including assaying its effects on mild cognitive impairments. Regarding cell types, raloxifene protects neurons from cell death, prevents glial activation, ameliorates myelin damage, and maintains health of endothelial cells. At whole central nervous system (CNS) levels, raloxifene ameliorated mild cognitive impairments, as seen in clinical trials, and showed beneficial effects in animal models of Parkinson’s disease. Moreover, with stroke and TBI in animal models, raloxifene showed curative effects. Furthermore, raloxifene showed healing effects regarding multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) in cell culture. The adverse biological signals typical of these conditions relate to neuronal activity, neurotransmitters and their receptors, plasticity, inflammation, oxidative stress, nitric oxide, calcium homeostasis, cell death, behavioral impairments, etc. Raloxifene favorably modulates these signals toward cell health—on the one hand, by modulating gene expression of the relevant proteins, for example by way of its binding to the cell nuclear estrogen receptors ERα and ERβ (genomic effects) and, on the other hand (nongenomic effects) by modulation of mitochondrial activity, reduction of oxidative stress and programmed cell death, maintaining metabolic balance, degradation of Abeta, and modulation of intracellular cholesterol levels. More specifically regarding Alzheimer’s disease, raloxifene may not cure diagnosed Alzheimer’s disease. However, the onset of Alzheimer’s disease may be delayed or arrested by raloxifene’s capability to attenuate mild cognitive impairment. Mild cognitive impairment is a condition that may precede diagnosis of Alzheimer’s disease. In this review, relatively new insights are addressed regarding the notion that Alzheimer’s disease can be caused by bacterial (as well as viral) infections, together with the most recent findings that raloxifene can counteract infections of at least some bacterial and viral strains. Thus, here, an overview of potential treatments of neurodegenerative disease by raloxifene is presented, and attention is paid to subcellular molecular biological pathways that may be involved.

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Amelioration of visual deficits and visual system pathology after mild TBI with the cannabinoid type-2 receptor inverse agonist SMM-189

Cited by 39 publications

References 94 publications

Endocannabinoid Modulation of Microglial Phenotypes in Neuropathology

Endocannabinoid Modulation of Microglial Phenotypes in Neuropathology

Indirect traumatic optic neuropathy after head trauma in adolescent male mice is associated with behavioral visual impairment, neurodegeneration, and elevated endoplasmic reticulum stress markers at acute and subacute times

Raloxifene as Treatment for Various Types of Brain Injuries and Neurodegenerative Diseases: A Good Start

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