Protective Effects of a synthetic glycosaminoglycan mimetic (OTR4132) in a rat immunotoxic lesion model of septohippocampal cholinergic degeneration.

Using a partial hippocampal cholinergic denervation model, we assessed the effects of the RGTA® named OTR4132, a synthetic heparan-mimetic biopolymer with neuroprotective/neurotrophic properties. Long-Evans male rats were injected with the cholinergic immunotoxin 192 IgG-saporin into the medial septum/diagonal band of Broca (0.37 µg); vehicle injections served as controls. Immediately after surgery, OTR4132 was injected into the lateral ventricles (0.25 µg/5 µl/rat) or intramuscularly (1.5 mg/kg). To determine whether OTR4132 reached the lesion site, some rats received intracerebroventricular (ICV) or intramuscular (I.M.) injections of fluorescent OTR4132. Rats were sacrificed at 4, 10, 20, or 60 days post-lesion (DPL). Fluorescein-labeled OTR4132 injected ICV or I.M. was found in the lesion from 4 to 20 DPL. Rats with partial hippocampal cholinergic denervation showed decreases in hippocampal acetylcholinesterase reaction products and in choline acetyltransferase-positive neurons in the medial septum. These lesions were the largest at 10 DPL and then remained stable until 60 DPL. Both hippocampal acetylcholinesterase reaction products and choline acetyltransferase-positive neurons in the medial septum effects were significantly attenuated in OTR4132-treated rats. These effects were not related to competition between OTR4132 and 192 IgG-saporin for the neurotrophin receptor P75 (p75NTR), as OTR4132 treatment did not alter the internalization of Cy3-labelled 192 IgG. OTR4132 was more efficient at reducing the acetylcholinesterase reaction products and choline acetyltransferase-positive neurons than a comparable heparin dose used as a comparator. Using the slice superfusion technique, we found that the lesion-induced decrease in muscarinic autoreceptor sensitivity was abolished by intramuscular OTR4132. After partial cholinergic damage, OTR4132 was able to concentrate at the brain lesion site possibly due to the disruption of the blood-brain barrier and to exert structural and functional effects that hold promises for neuroprotection/neurotrophism.

Effects of acute and chronic sleep deprivation on daytime alertness and cognitive performance of healthy snorers and non-snorers.

BACKGROUND: Respiratory events during sleep usually lead to micro arousals resulting in consecutive daytime sleepiness even in healthy snorers. The present study investigated the evolution of subjective and objective daytime sleepiness and reaction time in healthy snorers submitted to acute and chronic sleep deprivation. METHODS: Objective sleepiness was measured by the MSLT, subjective sleepiness by the Karolinska Sleepiness Scale (KSS), and reaction time (RT) by the Psychomotor Vigilance Test. Mean sleep latencies, KSS scores and performance were analyzed through repeated measures ANOVAs with one between-factor (snorers and non-snorers) and two within-factors (sleep deprivation [baseline, acute, and chronic sleep deprivation] and time-of-day). RESULTS: The findings reveal that sleep deprivation does not enhance snoring but that, during baseline, objective daytime sleepiness is higher in snorers than in non-snorers (shorter sleep latencies) with no difference in subjective assessments. The effects of acute and chronic sleep deprivation on sleep are similar in both groups, but, after acute sleep deprivation, RT and attentional lapses (RT >500 ms) are higher in snorers. Chronic sleep deprivation produces similar results in both groups. CONCLUSION: These results suggest that respiratory efforts may be involved in the increased vulnerability to sleep deprivation of healthy snorers when compared to non-snorers.

Living alongside railway tracks: Long-term effects of nocturnal noise on sleep and cardiovascular reactivity as a function of age.

Very few studies were devoted to permanent effects of nocturnal railway noise on sleep and cardiovascular reactivity. We investigated the effects of nocturnal railway noise on sleep and cardiovascular response in young and middle-aged adults living for many years either near a railway track or in a quiet area. Forty subjects (50% males) divided into two age groups (juniors: 26.2+/-3.6 and seniors: 56.2+/-4.2) participated in this experiment. Half of them lived near a railway track (RW group: 2.6 to 19 years) and the other half in a quiet environment (QE group: 8.1 to 14.2 years). After an adaptation night, all subjects underwent two nights in the laboratory: one control night and one noisy night (30 by-passes of a freight train). Sleep and cardiovascular modifications were assessed in response to noise. Sleep fragmentation indices were lower in RW subjects compared to QE whatever their age. In response to noise, there was a higher cardiovascular response rate to noise in RW juniors and a lower cardiovascular response rate in RW seniors compared to their age-paired QE counterparts. In conclusion, permanent exposure to nocturnal railway noise leads to decreased sleep fragmentation and to cardiovascular habituation. It is suggested that during the initial period experienced by residents living near railway tracks, nocturnal railway noise could induce a sensitization process on the autonomic response to noise reflecting a startle/defense reflex due to its functional significance, which progressively turns to habituation in the long-term if no adverse effect is experienced.

Cardiovascular responses to railway noise during sleep in young and middle-aged adults.

The aim of this study was to investigate the effects of nocturnal railway noise on cardiovascular reactivity in young (25.8 +/- 2.6 years) and middle-aged (52.2 +/- 2.5 years) adults during sleep. Thirty-eight subjects slept three nights in the laboratory at 1-week interval. They were exposed to 48 randomized pass-bys of Freight, Passenger and Automotive trains either at an 8-h equivalent sound level of 40 dBA (Moderate) and 50 dBA (High) or at a silent Control night. Heart rate response (HRR), heart response amplitude (HRA), heart response latency (HRL) and finger pulse response (FPR), finger pulse amplitude (FPA) and finger pulse latency (FPL) were recorded to measure cardiovascular reactivity after each noise onset and for time-matched pseudo-noises in the control condition. Results show that Freight trains produced the highest cardiac response (increased HRR, HRA and HRL) compared to Passenger and Automotive. But the vascular response was similar whatever the type of train. Juniors exhibited an increased HRR and HRA as compared to seniors, but there was no age difference on vasoconstriction, except a shorter FPL in seniors. Noise level produced dose-dependent effects on all the cardiovascular indices. Sleep stage at noise occurrence was ineffective for cardiac response, but FPA was reduced when noise occurred during REM sleep. In conclusion, our study is in favor of an important impact of nocturnal railway noise on the cardiovascular system of sleeping subjects. In the limit of the samples studied, Freight trains are the most harmful, probably more because of their special length (duration) than because of their speed (rise time).

Synthesis and rheological properties of hydrogels based on amphiphilic alginate-amide derivatives.

New amphiphilic derivatives of sodium alginate were prepared by covalent attachment of dodecylamine onto the polysaccharide via amide linkages at different substitution ratios, using 2-chloro-1-methylpyridinium iodide (CMPI) as coupling reagent. The aim was to limit the progressive loss of associative behaviour which occurs in the case of previously described dodecyl ester alginate derivatives due to hydrolysis of ester bonds. A series of hydrogels was obtained which differed by the amount of attached dodecyl tails. The stability and viscoelastic properties were evaluated and compared to those of hydrogels obtained with alginate esters. The observed differences were discussed in relation to the synthesis procedures. The advantages of amide links are underlined, especially with regard to long-term stability of hydrogels.

Structural and functional recovery elicited by combined putrescine and aminoguanidine treatment after aspirative lesion of the fimbria-fornix and overlying cortex in the adult rat.

Damage to the adult CNS often causes permanent deficits. Based on a lesion model of septohippocampal pathway aspiration in the rat, we attempted to promote neuronal cell survival and post-traumatic recovery by using a pharmacological treatment combining aminoguanidine and putrescine (AGP). The functional recovery was followed over 15 weeks before morphological analysis. AGP treatment produced a persistent attenuation (approximately 50%) of the lesion-induced hyperactivity, a reduction (approximately 60%) in the sensorimotor impairments and an improved performance in the water-maze task which did not, however, rely upon improved memory capabilities. AGP weakened the lesion-induced decrease in ChAT-positive neurons in the medial septum and the extent of thalamic retrograde necrosis (by approximately 30% in each case) and resulted in a partial cholinergic reinnervation of the dentate gyrus. These promising results support the idea that coadministration of putrescine and aminoguanidine might become a potent way to foster structural and functional recovery (or compensation) in the adult mammalian CNS after injury.

Polyamine and aminoguanidine treatments to promote structural and functional recovery in the adult mammalian brain after injury: a brief literature review and preliminary data about their combined administration.

The regeneration potential of the adult mammalian central nervous system (CNS) is very modest, due to, among other factors, the presence of either a glial scar, or myelin-associated regeneration inhibitors such as Nogo-A, MAG and OMgp, which all interact with the same receptor (NgR). After a brief review of the key proteins (Rho and PKC) implicated in NgR-mediated signalling cascades, we will tackle the implications of cAMP and Arginase I in overcoming myelin growth-inhibitory influence, and then will focus on the effects of polyamines and aminoguanidine to propose (and to briefly support this proposal by our own preliminary data) that their association might be a potent way to enable functionally-relevant regeneration in the adult mammalian CNS.

Hebb-Williams performance and scopolamine challenge in rats with partial immunotoxic hippocampal cholinergic deafferentation.

Recent studies suggested that the cholinergic innervation of the hippocampus is not crucial for spatial learning, but it might be important for other forms of learning. This study assessed the effects of partial immunotoxic cholinergic lesions in the medial septum and concurrent scopolamine challenge in a complex learning task, the Hebb-Williams maze. Long-Evans rats were given intraseptal injections of 192 IgG-saporin (SAPO). Rats injected with phosphate-buffered saline (PBS) served as controls. Starting 25 days after surgery, behavioural performance was assessed in the Hebb-Williams maze test without prior or after injection of scopolamine (0.17 or 0.5 mg/kg, i.p.). In SAPO rats, histochemical analysis showed a 40-45% decrease in the density of hippocampal AChE staining. The number of ChAT-positive cell bodies in the medial septum was also significantly decreased (-56%) and there was a non-significant reduction of the number of parvalbumine-positive neurons. The behavioural results demonstrated that the lesions induced small but significant learning deficits. At 0.17 mg/kg, scopolamine produced more impairments in SAPO rats than in PBS-injected rats, suggesting an additive effect between the partial lesion and the drug. These observations indicate that the Hebb-Williams test may be more sensitive to alterations of septohippocampal cholinergic function, than radial- or water-maze tasks. They also show that subtle learning deficits can be detected after partial lesions of the cholinergic septohippocampal pathways. Finally, the data from the scopolamine challenge are in keeping with clinical results showing higher sensitivity to muscarinic blockade in aged subjects in whom weaker cholinergic functions can be presumed.

Intraseptal injection of the 5-HT1A/5-HT7 agonist 8-OH-DPAT and working memory in rats.

RATIONALE: In rats, 5-HT(1A) receptors are present in the septal region, e.g. on cholinergic neurons of the medial septum, where they might be a substrate for cognitively relevant interactions between cholinergic and serotonergic systems. OBJECTIVE: The present experiment assessed the effects of the stimulation of septal 5-HT(1A) receptors on spatial working memory. METHODS: Stimulation of septal 5-HT(1A) receptors was carried out by infusions targetting the medial septum of the 5-HT(1A)/5-HT(7) receptor agonist 8-hydroxy-2-(di-n-propyl-amino)-tetralin (8-OH-DPAT; 0.5 or 4 microg). Spatial memory was assessed in a water maze using a protocol placing emphasis on spatial working memory. The location of the hidden platform was changed every day and performance was assessed on two consecutive trials each day. RESULTS: In comparison to vehicle injections, the intraseptal infusion of 4 microg 8-OH-DPAT impaired performance significantly: rats treated with 8-OH-DPAT exhibited increased distances to reach the hidden platform on both trials 1 and 2. Rats infused with 0.5 microg showed similar changes that failed to be significant. Such effects were not observed when the platform was visible. CONCLUSIONS: These results extend those of a previous experiment which showed that intraseptal injections of 8-OH-DPAT impaired spatial reference memory. Based on the characteristics of the observed deficits, it is suggested that the 8-OH-DPAT-induced impairment, rather than being only the result of a true alteration of working memory, might reflect a more global cognitive deficiency in which alteration of general memory capacities may be biased by disrupted search strategies/exploration and/or dysfunctions of attention.

Transplantation of neurospheres after granule cell lesions in rats: cognitive improvements despite no long-term immunodetection of grafted cells.

EGF-responsive C17 murine-derived neural stem cells (neurospheres) were grafted into the dentate gyrus of adult male rats after dentate granule cells lesions produced by colchicine injections. Behavioural performance was evaluated over two post-grafting periods, using tests sensitive to hippocampal dysfunctions. The first period began 1 month after grafting and testing conducted in the water maze and the radial maze distinguished working- and reference-memory performance. The second period began 9 months after grafting and learning performance was also evaluated in a Hebb-Williams maze, in addition to both other tests. The lesions induced lasting deficits in all tests. During the first period, the grafts had no effect in either test. Conversely, during the second period, grafted rats showed a weak improvement in the water maze and a significant increase of reference memory performance in the radial maze. In the Hebb-Williams maze, performance of grafted rats was close to normal. Strengthening the idea that dentate gyrus granule cells play an important role in the acquisition of new (perhaps more configural than only spatial) information, our results, moreover, suggest that neurosphere grafts may foster recovery after damage to point-to-point connection systems in the adult brain.

Prolactin induces SHP-2 association with Stat5, nuclear translocation, and binding to the beta-casein gene promoter in mammary cells.

The Src homology 2 (SH2) domain containing protein-tyrosine phosphatase SHP-2 contributes to prolactin receptor (PRLR) signal transduction to beta-casein gene promoter activation. We report for the first time that SHP-2 physically associates with the signal transducer and activator of transcription-5a (Stat5a), an important mediator of PRLR signaling to milk protein gene activation, in the mouse mammary HC11 and the human breast cancer T47D cells when stimulated with prolactin (PRL) and human growth hormone, respectively. In addition, overexpression studies indicate that the carboxyl-terminal SH2 domain of SHP-2 is required to maintain tyrosine phosphorylation of Stat5 and its interaction with SHP-2. Furthermore, we demonstrate by nuclear co-immunoprecipitation and indirect immunofluorescence studies that PRL stimulation of mammary cells leads to the nuclear translocation of SHP-2 as a complex with Stat5a. This process was found to involve the catalytic activity of the phosphatase. Finally, using the Stat5 GAS (gamma-activated sequence) element of the beta-casein gene promoter in electrophoretic mobility shift assays, we demonstrate that PRL induces the SHP-2-Stat5a complex to bind to DNA. The presence of the phosphatase in the protein-bound DNA complex was verified by using polyclonal antisera to SHP-2. Our studies indicate a tight physical and functional interaction between SHP2 and Stat5 required for regulation and perpetuation of PRL-mediated signaling in mammary cells and suggest a potential role for SHP-2 in the nucleus.