Search

HIV-associated neurocognitive disorders (HAND) have been linked to dysregulation of glutamate metabolism in the central nervous system (CNS) culminating in elevated extracellular glutamate and disrupted glutamatergic neurotransmission. Increased glutamate synthesis via upregulation of glutaminase (GLS) activity in brain immune cells has been identified as one potential source of excess glutamate in HAND. However, direct evidence for this hypothesis in an animal model is lacking, and the viability of GLS as a drug target has not been explored. In this brief report, we demonstrate that GLS inhibition with the glutamine analogue 6-diazo-5-oxo-L-norleucine (DON) can reverse cognitive impairment in the EcoHIV-infected mouse model of HAND. However, due to peripheral toxicity DON is not amenable to clinical use in a chronic disease such as HAND. We thus tested JHU083, a novel, brain penetrant DON prodrug predicted to exhibit improved tolerability. Systemic administration of JHU083 reversed cognitive impairment in EcoHIV-infected mice similarly to DON, and simultaneously normalized EcoHIV-induced increases in cerebrospinal fluid (CSF) glutamate and GLS activity in microglia-enriched brain CD11b + cells without observed toxicity. These studies support the mechanistic involvement of elevated microglial GLS activity in HAND pathogenesis, and identify JHU083 as a potential treatment option. Graphical Abstract Please provide Graphical Abstract caption.Glutamine Antagonist JHU083 Normalizes Aberrant Glutamate Production and Cognitive Deficits in the EcoHIV Murine Model of HIV-Associated Neurocognitive Disorders .

The original version of this article unfortunately contained a mistake in the text of the entire article. The word "IL-39" should read as "meteorin-like protein". This has been corrected with this correction.

Pancreatic cancer is the most lethal digestive cancer and the fourth leading cause of cancer death in the US. IL-39, a heterodimer of p19 and EBI3, is a newly found cytokine and its role in the pathogenesis of neoplasia has not been studied yet. This study was designed to investigate the direct role of IL-39 in the growth of pancreatic cancer. Clonogenic survival assay, cell proliferation, and caspase-3 activity kits were used to evaluate the direct effects of IL-39 on cell survival, proliferation and apoptosis of the widely studied pancreatic cancer cell line MiaPaCa-2. We further investigated the possible molecular mechanisms by using RT-PCR and IHC. The percentage of colonies of pancreatic cancer cells increased significantly in the presence of IL-39. This was paralleled with the increase in the OD value of cancer cells in the presence of IL-39. Interestingly, the relative caspase-3 activity in cancer cells decreased significantly in the presence of IL-39. Furthermore, the pro-tumor effect of IL-39 on pancreatic cancer cells correlated with decreased anti-proliferative molecule p21.The anti-apoptotic effect of IL-39 correlated with decreased pro-apoptotic molecule TRAILR1. These results suggest that IL-39 favors growth of pancreatic cancer by promoting growth and inhibiting apoptosis of cancer cells. This suggests that IL-39 acts as a friend to pancreatic cancer. Thus, inhibition of effect of IL-39 on cells might be a promising strategy to treat pancreatic cancer.

Insulin delivery to the brain has emerged as an important therapeutic target for cognitive disorders associated with abnormal brain energy metabolism. Although insulin is transported across the blood-brain barrier, peripheral routes of administration are problematic due to systemic effects of insulin on blood glucose. Intranasal (IN) administration is being investigated as an alternative route. We conducted a head-to-head comparison of subcutaneous (SC) and IN insulin, assessing plasma and brain pharmacokinetics and blood glucose levels in the mouse. SC insulin (2.4 IU) achieved therapeutically relevant concentrations in the brain (AUC brain = 2537 h·μIU/mL) but dramatically increased plasma insulin (AUC plasma = 520 351 h·*μIU/mL), resulting in severe hypoglycemia and in some cases death. IN administration of the same dose resulted in similar insulin levels in the brain (AUC brain = 3442 h·μIU/mL) but substantially lower plasma concentrations (AUC plasma = 354 h·μIU/mL), amounting to a ∼ 2000-fold increase in the AUC brain:plasma ratio relative to SC. IN dosing also had no significant effect on blood glucose. When administered daily for 9 days, IN insulin increased brain glucose and energy metabolite concentrations (e.g., adenosine triphosphate and phosphocreatine) without causing overt toxicity, suggesting that IN insulin may be a safe therapeutic option for cognitively impaired patients.

This Viewpoint is based on a recent panel featured at the 2017 Winter Conference on Brain Research in which the psychiatric comorbidities of HIV infection were discussed. Psychiatric comorbid conditions occur at high rates in HIV infected patients, complicating treatment and contributing to poor outcomes. A complex relationship between HIV infection and psychiatric comorbidity is an active area of investigation, but increased awareness of the impact of psychiatric complications of NeuroAIDS is needed in both the laboratory and the clinic to better understand and treat these interrelated conditions.

Fifty-three psychiatric patients, 16 with schizophrenia, 19 with affective disorder, and 19 with schizo-affective disorder were diagnosed by Research Diagnostic Criteria. Hoffmann reflex recovery curves were measured in the right and left legs of each patient. In both affective disorder and schizo-affective disorder, recovery curve height in the right and left legs was highly correlated. In schizophrenia, recovery curve height in the right and left legs was not correlated. These results demonstrate a right-left asymmetry in motor neuron excitability specific to schizophrenia. The findings are compatible with a deficit in hemispheric transfer that is unique to schizophrenia. Other interpretations can be made, including diffuse cortical or subcortical dysfunction in schizophrenia which disrupts transfer or interpretation or intrahemispheric communication.

Two groups of congenitally deaf and two groups of hearing right-handed subjects identified pairs of nonsense shapes and letters after simultaneous bilateral tactual exploration. In response to shapes, left and right hand pointing to multiple choice arrays were compared. Three response modes, writing and left and right and fingerspelling, were compared for letters. A tendency for right tactual field superiority for shapes was observed in all groups. Groups initially exposed to letters showed significant right field superiority across response modes for shapes. No left-right asymmetries were observed for letters. Differences due to deafness were not observed.

Recovery curves of the Hoffmann reflex (H reflex) were measured in both legs of 10 unmedicated inpatients with schizoaffective disorder, depressed type. Neither recovery curve height of the right leg nor that of the left leg was significantly correlated with clinical psychopathology, although a consistent negative relation was noted between recovery curve height of the left leg and psychopathology. Right-left differences in recovery curve height significantly correlated with both Brief Psychiatric Rating Scale and Hamilton Rating Scale for Depression ratings of psychopathology, such that relative elevation of the recovery curve of the right leg or relative lowering of the recovery curve of the left leg correlated with symptom severity. Three patients who later developed psychotic symptoms when treated with bupropion, a dopaminergic agent, had lower recovery curves, indicative of increased central dopaminergic activity. Relatively lower left-sided recovery curves may reflect increased dopaminergic activity on the right side of the brain in schizoaffective disorder, compared to the left in schizophrenia.

In an open study, 20 patients with schizo-affective disorder, depressed type, were randomly assigned to treatment with either bupropion alone or bupropion combined with haloperidol. Bupropion plus haloperidol was significantly more efficacious than bupropion alone, as judged by improvement in clinical ratings on the Hamilton Depression Scale and the Brief Psychiatric Rating Scale. Of 9 patients treated with bupropion alone, 3 experienced exacerbation of psychotic symptoms. While treatment of schizo-affective disordered patients with bupropion and haloperidol is efficacious, the use of bupropion alone carries a significant risk of exacerbation of psychotic symptoms. This finding is probably related to bupropion's dopaminergic effects. Further work is needed to evaluate the relative contribution of bupropion to the improvement in schizo-affective patients treated with both bupropion and haloperidol.

Thirty-six hospitalized patients with schizophrenia or schizo-affective disorder who were judged unresponsive to conventional treatment were tested 5 days after last receiving medication and retested 4 weeks after treatment with thiothixene, loxapine, or molindone. Cortical laterality for linguistic and motor functions was measured by visual half-field (VHF) recognition of words, dichotic listening (DL), the Crawford Small Parts (CSP) performance test, and finger-tapping (FT) dexterity. The recovery curve of the Hoffmann reflex was measured in both legs and lateral asymmetries of the recovery curve were calculated as lateralization coefficients. Cortical laterality measurements were also performed in 36 control subjects. Cortical laterality measures of patients were not significantly different from those of control subjects and were not related to measures of clinical symptomatology. The height of the H-reflex recovery curve (mean of both legs) was not related to clinical symptomatology. Recovery curve height of the right leg only was significantly correlated with the withdrawal-retardation (R) subscale of the Brief Psychiatric Rating Scale (BPRS). Recovery curve height was significantly correlated with number of schizophrenic symptoms recorded for diagnosis based on the Research Diagnostic Criteria (RDC). Recovery curve height (mean of both legs) in medicated patients was significantly correlated with right sided preference as measured by both VHF and DL. In unmedicated patients, lateralization of the recovery curve was correlated with clinical symptomatology, such that relative elevations of the right leg were associated with higher scores of the R subscale of the BPRS, while relative elevations of the left leg were associated with higher scores of the anxious-depression (D) subscale of the BPRS. Left hemispheric or subcortical dysfunction, manifested by recovery curve elevation of the right leg, was related to schizophrenic symptomatology (R subscale). Right hemispheric or subcortical dysfunction, manifested by relative recovery curve elevation in the left leg, was related to depression symptomatology (D subscale). These findings are compatible with asymmetries of subcortical amine function in schizophrenia and schizo-affective disorder.

Lateral asymmetry of the Hoffmann reflex (H-reflex) recovery curve was found in seven subjects with no personal or family history of neurological or psychiatric disorder. Differences between recovery curves from the right and left leg were larger than differences in the same leg on two successive test days. In a group of 27 psychiatric inpatients, lateral asymmetry of the later portion of the recovery curve was correlated with cortical laterality, as measured by selective identification of differing verbal stimuli presented simultaneously to both ears (DL) and to total laterality scores, a sum of visual half-field, DL, and motor laterality scores. Asymmetry of the recovery curve is related in part to cortical laterality, possibly through selective activation of cortical motor centres on the preferred side.

Cebus albifrons monkeys received electrical stimulation of the hindlimbs over a wide range of intensities. On trials signalled by a blue light, the animals were permitted to escape shock by pressing a disc, or shock was terminated after 8 sec (free escape). Escape force (disc pressure) was found to increase as stimulation intensity increased well beyond escape threshold, while shock duration curves reached plateau at the mid-range of intensities. The shock duration curves generated by free escape responses should be comparable to pain detection functions obtained by similar operations in humans, and the curves were stable over months of testing, as is generally found in pain-detection studies. On trials signalled by a red light, the animals received intense tail shock immediately after escape responses (punished escape), or, if they endured leg shock for 8 sec without escaping, then they could avoid tail shock with a panel press. The shock duration curves generated by punished escape responses should be comparable to pain tolerance functions as defined for human subjects, and the escape thresholds were considerably higher on red-light trials. As in human studies, the tolerance curves were not stable over repeated testing sessions, and some feature of the paradigm forced a progression toward extremely high levels of tolerance.