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Journal of Neurovirology Apr 2018Most studies of HIV latency focus on the peripheral population of resting memory T cells, but the brain also contains a distinct reservoir of HIV-infected cells in...
Most studies of HIV latency focus on the peripheral population of resting memory T cells, but the brain also contains a distinct reservoir of HIV-infected cells in microglia, perivascular macrophages, and astrocytes. Studying HIV in the brain has been challenging, since live cells are difficult to recover from autopsy samples and primate models of SIV infection utilize viruses that are more myeloid-tropic than HIV due to the expression of Vpx. Development of a realistic small animal model would greatly advance studies of this important reservoir and permit definitive studies of HIV latency. When radiation or busulfan-conditioned, immune-deficient NSG mice are transplanted with human hematopoietic stem cells, human cells from the bone marrow enter the brain and differentiate to express microglia-specific markers. After infection with replication competent HIV, virus was detected in these bone marrow-derived human microglia. Studies of HIV latency in this model would be greatly enhanced by the development of compounds that can selectively reverse HIV latency in microglial cells. Our studies have identified members of the CoREST repression complex as key regulators of HIV latency in microglia in both rat and human microglial cell lines. The monoamine oxidase (MAO) and potential CoREST inhibitor, phenelzine, which is brain penetrant, was able to stimulate HIV production in human microglial cell lines and human glial cells recovered from the brains of HIV-infected humanized mice. The humanized mice we have developed therefore show great promise as a model system for the development of strategies aimed at defining and reducing the CNS reservoir.
Topics: AIDS Dementia Complex; Animals; Anti-HIV Agents; Bone Marrow Cells; Brain; Busulfan; Cell Differentiation; Co-Repressor Proteins; Disease Models, Animal; Gene Expression Regulation; HIV-1; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Mice; Mice, Transgenic; Microglia; Monoamine Oxidase Inhibitors; Nerve Tissue Proteins; Phenelzine; Rats; Repressor Proteins; Transplantation, Heterologous; Virus Latency; Whole-Body Irradiation
PubMed: 29256041
DOI: 10.1007/s13365-017-0604-2 -
Journal of Neuroinflammation Jun 2016Chronic neuropathic pain is a common symptom of multiple sclerosis (MS). MOG35-55-induced experimental autoimmune encephalomyelitis (EAE) has been used as an animal...
BACKGROUND
Chronic neuropathic pain is a common symptom of multiple sclerosis (MS). MOG35-55-induced experimental autoimmune encephalomyelitis (EAE) has been used as an animal model to investigate the mechanisms of pain in MS. Previous studies have implicated sensitization of spinal nociceptive networks in the pathogenesis of pain in EAE. However, the involvement of supraspinal sites of nociceptive integration, such as the primary somatosensory cortex (S1), has not been defined. We therefore examined functional, structural, and immunological alterations in S1 during the early stages of EAE, when pain behaviors first appear. We also assessed the effects of the antidepressant phenelzine (PLZ) on S1 alterations and nociceptive (mechanical) sensitivity in early EAE. PLZ has been shown to restore central nervous system (CNS) tissue concentrations of GABA and the monoamines (5-HT, NA) in EAE. We hypothesized that PLZ treatment would also normalize nociceptive sensitivity in EAE by restoring the balance of excitation and inhibition (E-I) in the CNS.
METHODS
We used in vivo flavoprotein autofluorescence imaging (FAI) to assess neural ensemble responses in S1 to vibrotactile stimulation of the limbs in early EAE. We also used immunohistochemistry (IHC), and Golgi-Cox staining, to examine synaptic changes and neuroinflammation in S1. Mechanical sensitivity was assessed at the clinical onset of EAE with Von Frey hairs.
RESULTS
Mice with early EAE exhibited significantly intensified and expanded FAI responses in S1 compared to controls. IHC revealed increased vesicular glutamate transporter (VGLUT1) expression and disrupted parvalbumin+ (PV+) interneuron connectivity in S1 of EAE mice. Furthermore, peri-neuronal nets (PNNs) were significantly reduced in S1. Morphological analysis of excitatory neurons in S1 revealed increased dendritic spine densities. Iba-1+ cortical microglia were significantly elevated early in the disease. Chronic PLZ treatment was found to normalize mechanical thresholds in EAE. PLZ also normalized S1 FAI responses, neuronal morphologies, and cortical microglia numbers and attenuated VGLUT1 reactivity-but did not significantly attenuate the loss of PNNs.
CONCLUSIONS
These findings implicate a pro-excitatory shift in the E-I balance of the somatosensory CNS, arising early in the pathogenesis EAE and leading to large-scale functional and structural plasticity in S1. They also suggest a novel antinociceptive effect of PLZ treatment.
Topics: Animals; Antidepressive Agents; Calcium-Binding Proteins; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Freund's Adjuvant; Hyperalgesia; Mice; Mice, Inbred C57BL; Microfilament Proteins; Myelin-Oligodendrocyte Glycoprotein; Neuralgia; Neurons; Pain Measurement; Pain Threshold; Parvalbumins; Peptide Fragments; Phenelzine; Plant Lectins; Receptors, N-Acetylglucosamine; Somatosensory Cortex; Synapses
PubMed: 27282914
DOI: 10.1186/s12974-016-0609-4 -
Brain Research Oct 2017During typical late-postnatal CNS development, net reductions in dendritic spine densities are associated with activity-dependent learning. Prior results showed agonist...
Chronic CB1 cannabinoid receptor antagonism persistently increases dendritic spine densities in brain regions important to zebra finch vocal learning and production in an antidepressant-sensitive manner.
During typical late-postnatal CNS development, net reductions in dendritic spine densities are associated with activity-dependent learning. Prior results showed agonist exposure in young animals increased spine densities in a subset of song regions while adult exposures did not, suggesting endocannabinoid signaling regulates dendritic spine dynamics important to vocal development. Here we addressed this question using the CB1 receptor-selective antagonist SR141716A (SR) to disrupt endocannabinoid signaling both during and after vocal learning. We hypothesized antagonist exposure during vocal development, but not adulthood, would alter spine densities. Following 25days of exposure and a 25day maturation period, 3D reconstructions of Golgi-Cox stained neurons were used to measure spine densities. We found antagonist treatments during both age periods increased densities within Area X (basal ganglia) and following adult treatments within HVC (premotor cortical-like). Results suggest both inappropriate cannabinoid receptor stimulation and inhibition are capable of similar disregulatory effects during establishment of circuits important to vocal learning, with antagonism extending these effects through adulthood. Given clinical evidence of depressant effects of SR, we tested the ability of the antidepressant monoamine oxidase inhibitor (MAOI) phenelzine to mitigate SR-induced spine density increases. This was confirmed implicating interaction between monoamine and endocannabinoid systems. Finally, we evaluated acute effects of these drugs to alter ability of novel song exposure to increase spine densities in auditory NCM and other regions, finding when combined, SR and phenelzine increased densities within Area X. These results contribute to understanding relevance of dendritic spine dynamics in neuronal development, drug abuse, and depression.
Topics: Animals; Antidepressive Agents; Brain; Cannabinoid Receptor Antagonists; Cannabinoids; Dendritic Spines; Endocannabinoids; Finches; Learning; Male; Monoamine Oxidase Inhibitors; Neurogenesis; Receptor, Cannabinoid, CB1; Vocalization, Animal
PubMed: 28743448
DOI: 10.1016/j.brainres.2017.07.015 -
Case Reports in Medicine 2015A 27-year-old Caucasian female with a history of depression was admitted to our local hospital with vague events that occurred a day before. This included an episode of...
A 27-year-old Caucasian female with a history of depression was admitted to our local hospital with vague events that occurred a day before. This included an episode of dysarthria, and unsteadiness, followed by feeling generally unwell. Two weeks prior to presentation she was commenced on phenelzine. During clinical assessment she suddenly deteriorated with a dramatic fall in her conscious level. Moreover, she became hyperthermic, tachycardic, and diaphoretic, and developed increased tone in all muscles and ocular clonus. Rectal diazepam was administered but failed to control the symptoms. Consequently, she was transferred to the intensive care unit for intubation and muscle relaxants were commenced. She responded well and recovered next day without complications. Her symptoms and signs were consistent with the serotonin syndrome with phenelzine being the likely cause. To the best of our knowledge, this is the first reported case to associate the condition with phenelzine alone at therapeutic dose.
PubMed: 25861278
DOI: 10.1155/2015/931963 -
Scientific Reports Mar 2024We have previously shown that the pro-oxidative aldehyde acrolein is a critical factor in MS pathology. In this study, we found that the acrolein scavenger hydralazine...
We have previously shown that the pro-oxidative aldehyde acrolein is a critical factor in MS pathology. In this study, we found that the acrolein scavenger hydralazine (HZ), when applied from the day of induction, can suppress acrolein and alleviate motor and sensory deficits in a mouse experimental autoimmune encephalomyelitis (EAE) model. Furthermore, we also demonstrated that HZ can alleviate motor deficits when applied after the emergence of MS symptoms, making potential anti-acrolein treatment a more clinically relevant strategy. In addition, HZ can reduce both acrolein and MPO, suggesting a connection between acrolein and inflammation. We also found that in addition to HZ, phenelzine (PZ), a structurally distinct acrolein scavenger, can mitigate motor deficits in EAE when applied from the day of induction. This suggests that the likely chief factor of neuroprotection offered by these two structurally distinct acrolein scavengers in EAE is their common feature of acrolein neutralization. Finally, up-and-down regulation of the function of aldehyde dehydrogenase 2 (ALDH2) in EAE mice using either a pharmacological or genetic strategy led to correspondent motor and sensory changes. This data indicates a potential key role of ALDH2 in influencing acrolein levels, oxidative stress, inflammation, and behavior in EAE. These findings further consolidate the critical role of aldehydes in the pathology of EAE and its mechanisms of regulation. This is expected to reinforce and expand the possible therapeutic targets of anti-aldehyde treatment to achieve neuroprotection through both endogenous and exogenous manners.
Topics: Mice; Animals; Acrolein; Encephalomyelitis, Autoimmune, Experimental; Neuroprotection; Phenelzine; Aldehydes; Inflammation; Mice, Inbred C57BL
PubMed: 38472318
DOI: 10.1038/s41598-024-56035-z -
Journal of Pharmacology &... 2016An infrequent manifestation of monoamine oxidase inhibitor (MAOI) toxicity is "ping-pong gaze" (PPG). We describe the case of a 26-year-old female who was found...
An infrequent manifestation of monoamine oxidase inhibitor (MAOI) toxicity is "ping-pong gaze" (PPG). We describe the case of a 26-year-old female who was found unresponsive after taking 40 tablets of phenelzine. On presentation to the hospital, her eyes were moving in characteristic "ping pong" fashion. After 6 hours her gaze terminated. The following day her neurologic exam was benign and she had no long-term sequelae. While the etiology of PPG is unknown, it is most often seen with irreversible structural brain damage. However, a detailed literature review revealed that previous cases of MAOI toxicity where the patient survived have all had complete neurologic recovery.
PubMed: 27127395
DOI: 10.4103/0976-500X.179360 -
Clinical Pharmacology : Advances and... 2021[This retracts the article DOI: 10.2147/CPAA.S67271.].
[This retracts the article DOI: 10.2147/CPAA.S67271.].
PubMed: 33688272
DOI: 10.2147/CPAA.S308255 -
Clinical Pharmacology : Advances and... 2020
PubMed: 32425620
DOI: 10.2147/CPAA.S240229