Endocrinology, diabetes and metabolism journal最新文献

Aims: Neuroinflammation complicates traumatic brain injury predisposing to long-lasting neurologic impairment. The aim of the present study was to test whether parenteral administration a small peptide mimic (SN..8) of the receptor- activating- region of the human serotonin 2A receptor (1-, 3- and 5-days) after traumatic brain injury suppresses hippocampal inflammation in the rat compared to a scrambled peptide sequence of the same eight amino acids.

Methods: Adult male Sprague-Dawley rats were exposed to lateral fluid percussion (LFP)-induced, traumatic brain injury (TBI) vs. sham injury. An identical 2 mg/kg concentration of SN..8 vs LD..8 (scrambled peptide) was administered via intraperitoneal route 1-, 3- and 5-days after injury. Two weeks post injury, the bilateral hippocampal, dorsal and ventral brain regions were examined by RT-PCR for altered gene expression. Comparisons were made between TBI vs sham injury; and active vs scrambled peptide treatment.

Results: Two weeks after injury, the novel SN..8 peptide (vs scrambled peptide) significantly reduced (more than 3-fold) CD68 mRNA relative expression in ventral hippocampus in adult male Sprague-Dawley rats subjected to TBI (N=22) (1.65 ± 0.83 vs 5.27 ± 4.1; P=0.012).

Conclusion: These results suggest that the neuroprotective effects of SN..8 peptide may be due in part to its ability to substantially suppress subacute inflammation in the ventral hippocampus.

Aims: Behavioral pattern separation is a hippocampal-dependent component of episodic memory and a sensitive marker of early cognitive decline. Here we tested whether mild traumatic injury causes loss of pattern separation in the rat and for its prevention by a novel neuroprotective peptide fragment of the human serotonin 2A receptor (SN..8).

Methods: Lateral fluid percussion was used to induce mild traumatic brain injury in male Sprague- Dawley rats. Rats were trained to distinguish between a stable vs unstable swim platform separated by increasing distances (4.5 vs 3.0 vs 1.5 feet) in a modification to the classic Morris water maze. Peptide SN..8 vs scrambled version of same amino acids (2 mg/kg) was administered via intraperitoneal route (1-, 3- and 5-days) after lateral fluid percussion or sham injury. Rats received three weeks of training and two weeks of testing before injury and were tested again at 2 and 5-weeks after injury.

Results: There was a gradient of decreasing incorrect responses to the choice between (stable vs unstable platform) as the platform separation distance was increased from 1.5 to 3.0 to 4.5 feet consistent with behavioral pattern separation. Systemic administration of SN..8 peptide (vs scrambled) peptide was associated with statistically significant lower rate of incorrect responses (at both 4.5 feet and 3.0 feet platform separation) in traumatic brain-injured rats (but not in sham-injured rats) tested at 2-weeks post-injury. Five weeks after injury, the rats had largely recovered and exhibited a much lower overall rate of incorrect responses across both drug and injury subgroups.

Conclusions: Introduction of an unstable platform (choice phase of the Morris water maze) at varying distances from the stable platform resulted in behavior having the hallmark of pattern separation. Our data are the first to suggest that systemic administration of (2 mg/kg) SN..8 peptide immediately after mild traumatic brain injury (lateral fluid percussion) appeared to protect against loss of behavioral pattern separation in the rat.

Aims: Accelerated cognitive decline frequently complicates traumatic brain injury. Obesity and type 2 diabetes mellitus drive peripheral inflammation which may accelerate traumatic brain injury-associated neurodegeneration. The Zucker rat harbors G-protein coupled receptor agonist IgG autoantibodies and in vitro neurotoxicity caused by these autoantibodies was prevented by a novel synthetic fragment of the serotonin 2A receptor. The aim of the present study was to test whether genetic obesity manifested in Zucker diabetic fatty rat is associated with greater spatial memory impairment before and after mild traumatic brain injury compared to Zucker lean rats. Furthermore, we investigated whether these neurodegenerative complications can be lessened by administration of a novel putative neuroprotective peptide comprised of a fragment of the second extracellular loop of the serotonin 2A receptor.

Methods: Age-matched lean and fatty diabetic Zucker rats were tested in the Morris water maze (spatial memory) prior to receiving a sham-injury or lateral fluid percussion (LFP) mild traumatic brain injury. Behavioral testing was repeated at 1-week, 1-month, and 3-month intervals following injury. A synthetic peptide consisting of a portion of the 5-hydroxytryptamine (serotonin) 2A receptor (2 mg/kg) (vehicle, or an inactive scrambled version of the peptide (2 mg/kg)) was administered via intraperitoneal route every other day for 7 days after sham or LFP injury to lean rats or 7 days before and after sham or LFP injury to fatty rats.

Results: Mild traumatic brain injury impaired recall of spatial memory in fatty and lean rats. Zucker fatty rats subjected to sham-injury or mild TBI experienced a significantly greater longitudinal decline in recall of spatial memory compared to lean Zucker rats. A synthetic peptide fragment of the 5-hydroxytryptamine 2A receptor significantly enhanced acquisition of spatial learning and it appeared to strengthen recall of spatial learning (one-week) after sham injury in Zucker rats.

Conclusions: These data suggest that the Zucker diabetic fatty rat is a suitable animal model to investigate the role of metabolic factor(s) in accelerated cognitive decline. A novel synthetic peptide comprised of a fragment of the second extracellular loop of the human serotonin 2A receptor appeared to have neuroprotective effects on both acquisition and recall of spatial memory in subsets of Zucker rats, with relatively greater benefit in sham-injured, lean Zucker rats.

Objectives: Traumatic brain injury (TBI) was associated with increased plasma agonist autoantibodies targeting the serotonin 2A receptor. Repeated TBI exposure is associated with high risk for neurodegenerative and neuropsychiatric complications. Here we tested a hypothesis that repeated TBI is associated with plasma agonist autoantibodies targeting more than one kind of catecholamine G-protein coupled receptor.

Methods: Protein-A affinity chromatography was used to isolate the IgG fraction of plasma in forty-two middle-aged and older adults who had experienced one or more TBI exposures. The Ig (1/40^th dilution=7.5 ug/mL) were tested for neurotoxicity in mouse neuroblastoma cells using an acute neurite retraction assay indicative of Gq11/IP3/Ca2+ and RhoA/Rho kinase signaling pathways' activation. Three different linear synthetic peptides corresponding to the second extracellular loop of the alpha 1A, alpha 2A or serotonin 2A receptors were used as target antigen in different enzyme-linked immunoassays. The second extracellular loop receptor peptides themselves (alpha 1A, alpha 2A) or a fragment (serotonin 2A) were tested for ability to prevent Ig-induced neurite retraction.

Results: Patients who had experienced either repeated TBI (N=10) or a single TBI with a co-morbid autoimmune disease (N=5) were significantly more likely to harbor neurotoxic plasma autoantibodies targeting both alpha 1 adrenergic and serotonin 2A receptors vs. patients having only a single TBI. Ig-induced neurotoxicity was significantly prevented by co-incubation with either 850 nM prazosin (alpha 1 adrenergic receptor) and/or 500 nM M100907 (serotonin 2A receptor) antagonists. Alpha 1 adrenergic receptor and serotonin 2A receptor Ig immunoreactive level and titer were significantly increased in repeated TBI and single TBI/autoimmune patients (N=7-8) compared to age-matched TBI patients without neurotoxic plasma Ig (N=4). SN.8, a linear synthetic peptide corresponding to a conserved region of the second extracellular loop (ECL) of the serotonin 2A receptor completely prevented neurite retraction induced by repeated TBI plasma Ig. A repeated TBI patient harboring alpha adrenergic receptor AAB alone experienced prospective steep decline in cognitive function over two years.

Conclusions: Repeated TBI and TBI with associated autoimmunity harbored more than one kind of neurotoxic catecholaminergic agonist GPCR autoantibody each associated with high risk for steep rate of cognitive decline. Specific immunoassays using the second extracellular receptor loop as target antigen are needed to detect each specific different GPCR autoantibody. A fragment of the second ECL of the serotonin 2A receptor (SN.8) neutralized Ig-induced neurotoxicity in repeated TBI or TBI with associated systemic autoimmunity.