The Reindeer Circadian Clock Is Rhythmic and Temperature-compensated But Shows Evidence of Weak Coupling Between the Secondary and Core Molecular Clock Loops.

Circadian rhythms synchronize the internal physiology of animals allowing them to anticipate daily changes in their environment. Arctic habitats may diminish the selective advantages of circadian rhythmicity by relaxing daily rhythmic environmental constraints, presenting a valuable opportunity to study the evolution of circadian rhythms. In reindeer, circadian control of locomotor activity and melatonin release is weak or absent, and the molecular clockwork is reportedly non-functional.

Tanycytes from a bird's eye view: gene expression profiling of the tanycytic region under different seasonal states in the Svalbard ptarmigan.

In mammals and birds, tanycytes are known to regulate thyroid hormone conversion, and this process is central to the control of seasonal reproduction. In mammals, this cell type is also implicated in retinoic acid signalling, neurogenesis, and nutritional gatekeeping, all of which have been linked to hypothalamic regulation of energy metabolism. Less is known about these potential wider roles of tanycytes in birds.

Seasonal food intake and energy balance: Neuronal and non-neuronal control mechanisms.

Animals inhabiting temperate and high latitudes undergo drastic seasonal changes in energy storage, facilitated by changes in food intake and body mass. Those seasonal changes in the animal's biology are not mere consequences of environmental energy availability but are anticipatory responses to the energetic requirements of the upcoming season and are actively timed by tracking the annual progression in photoperiod. In this review, we discuss how photoperiod is used to control energy balance seasonally and how this is distinct from energy homeostasis.

Biological timekeeping in polar environments: lessons from terrestrial vertebrates.

The polar regions receive less solar energy than anywhere else on Earth, with the greatest year-round variation in daily light exposure; this produces highly seasonal environments, with short summers and long, cold winters. Polar environments are also characterised by a reduced daily amplitude of solar illumination. This is obvious around the solstices, when the Sun remains continuously above (polar 'day') or below (polar 'night') the horizon.

Ambient Temperature Effects on the Spring and Autumn Somatic Growth Trajectory Show Plasticity in the Photoneuroendocrine Response Pathway in the Tundra Vole.

Seasonal mammals register photoperiodic changes through the photoneuroendocrine system enabling them to time seasonal changes in growth, metabolism, and reproduction. To a varying extent, proximate environmental factors like ambient temperature (T) modulate timing of seasonal changes in physiology, conferring adaptive flexibility. While the molecular photoneuroendocrine pathway governing the seasonal responses is well defined, the mechanistic integration of nonphotoperiodic modulatory cues is poorly understood.

Evidence for circadian-based photoperiodic timekeeping in Svalbard ptarmigan, the northernmost resident bird.

The high Arctic archipelago of Svalbard (74°-81° north) experiences extended periods of uninterrupted daylight in summer and uninterrupted night in winter, apparently relaxing the major driver for the evolution of circadian rhythmicity. Svalbard ptarmigan (Lagopus muta hyperborea) is the only year-round resident terrestrial bird species endemic to the high Arctic and is remarkably adapted to the extreme annual variation in environmental conditions. Here, we demonstrate that, although circadian control of behavior disappears rapidly upon transfer to constant light conditions, consistent with the loss of daily activity patterns observed during the polar summer and polar night, Svalbard ptarmigans nonetheless employ a circadian-based mechanism for photoperiodic timekeeping.

Mechanisms of temperature modulation in mammalian seasonal timing.

Global warming is predicted to have major effects on the annual time windows during which species may successfully reproduce. At the organismal level, climatic shifts engage with the control mechanism for reproductive seasonality. In mammals, laboratory studies on neuroendocrine mechanism emphasize photoperiod as a predictive cue, but this is based on a restricted group of species.

Body Temperature and Activity Rhythms Under Different Photoperiods in High Arctic Svalbard ptarmigan ().

Organisms use circadian rhythms to anticipate and exploit daily environmental oscillations. While circadian rhythms are of clear importance for inhabitants of tropic and temperate latitudes, its role for permanent residents of the polar regions is less well understood. The high Arctic Svalbard ptarmigan shows behavioral rhythmicity in presence of light-dark cycles but is arrhythmic during the polar day and polar night.

Evaluation of Homobivalent Carbolines as Designed Multiple Ligands for the Treatment of Neurodegenerative Disorders.

Neurodegenerative diseases represent a challenge for biomedical research due to their high prevalence and lack of mechanism-based treatments. Because of the complex pathology of neurodegenerative disorders, multifunctional drugs have been increasingly recognized as potential treatments. We identified homobivalent γ-carbolinium salts as potent inihitors of both cholinesterases, N-methyl-D-aspartate receptors, and monoamine oxidases.

Beta and gamma carboline derivatives as potential anti-Alzheimer agents: A comparison.

Nine novel β- and γ-carboline derivatives bearing either methyl-, propargyl- or phenethyl-residues at the indole nitrogen were synthesized and tested as potential anti-Alzheimer drugs. Antagonism of recombinantly expressed NMDA receptors, inhibition of cholinesterases, and radical scavenging properties were determined for all compounds. Some were additionally tested in vivo for their ability to reverse scopolamine-induced cognitive impairment in an 8-arm radial maze experiment with rats.

9-Methyl-β-carboline-induced cognitive enhancement is associated with elevated hippocampal dopamine levels and dendritic and synaptic proliferation.

β-Carbolines (BCs) belong to the heterogenous family of carbolines, which have been found exogenously, that is, in various fruits, meats, tobacco smoke, alcohol and coffee, but also endogenously, that is, blood, brain and CSF. These exogenous and endogenous BCs and some of their metabolites can exert neurotoxic effects, however, an unexpected stimulatory effect of 9-methyl-β-carboline (9-me-BC) on dopaminergic neurons in primary mesencephalic cultures was recently discovered. The aim of the present study was to extend our knowledge on the stimulatory effects of 9-me-BC and to test the hypothesis that 9-me-BC may act as a cognitive enhancer.

Ultrastructural and ultraimmunohistochemical changes upon partial nephrectomy and uranyl intoxication in the rat kidney.

We studied kidneys of rats intoxicated with uranylnitrate (UN) or subjected to 5/6 nephrectomy (NX) or after a combination of both procedures (NX-UN). Our observations indicate that UN causes impressive changes of ultrastructure (partial loss of brush border, appearance of intercellular clefts in the epithelial barrier) and altered protein expression (α-SMA, collagen I and III) in proximal tubule cells. Renal parameters (creatinine clearance, proteinuria) seemed to be unaffected.

Investigation into the in vivo effects of five novel tacrine/ferulic acid and beta-carboline derivatives on scopolamine-induced cognitive impairment in rats using radial maze paradigm.

Two tacrine-ferulic acid hybrids (1 A, 1 B) and three beta-carboline derivatives (BCs; 2A, 2B, 2C) were tested in vivo on 3-month-old female rats as multi-potent anti-Alzheimer drug candidates. In vitro, the two tacrine-ferulic acid hybrids show higher acetylcholinesterase (AChE) inhibitory activity and comparable butyrylcholinesterase (BChE) inhibitory activity compared to tacrine (CAS 1684-40-8). However, in vivo both substances have no beneficial effect on scopolamine (CAS 51-34-3) induced cognition impairment.

Influence of age on cognition and scopolamine induced memory impairment in rats measured in the radial maze paradigm.

The influence of age on (1) cognition and (2) scopolamine (CAS 51-34-3) induced memory impairment in female rats was measured in the radial maze paradigm (RAM). (1) First training trials were done with 3 and 12 months old rats. Rats were trained to find all eight food baits in the RAM without errors and within 1 min.

Tacrine-NO donor and tacrine-ferulic acid hybrid molecules as new anti-Alzheimer agents: hepatotoxicity and influence on the cytochrome P450 system in comparison to tacrine.

Tacrine (CAS 321-64-2) is a reversible acetylcholine esterase inhibitor that, despite exerting beneficial effects on Alzheimer's disease (AD), displays marked hepatotoxicity. Searching for safer drugs and taking into account the multi-pathogenesis of AD, two tacrine-NO donor hybrid molecules (FL16, FL38) as well as a tacrine-ferulic acid hybrid (FL67) were synthesized. NO donors coupled to the tacrine moiety may exert an additional beneficial effect on AD via an increased blood supply to the brain and by reducing inflammation.

A new way of data interpretation for cognition tests in rats used to characterise six choline esterase inhibitors with heterocyclic nitrogen bridgehead structure. Application in Alzheimer therapy.

Six new tri- and tetracyclic nitrogen bridgehead compounds known to be moderate to potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro were tested in vivo as experimental therapeutics for treatment of Alzheimer's disease. Cognitive impairment in rats was reversibly induced by scopolamine (CAS 51-34-3). The effect of the new substances was evaluated in an eight-arm radial maze and run times (1), errors (2), correct choices (3), correct choices per second (4), speed (5), and running distance (6) were recorded.

NO-donating tacrine hybrid compounds improve scopolamine-induced cognition impairment and show less hepatotoxicity.

A series of tacrine-NO donor hybrid compounds are synthesized and evaluated for cholinesterase inhibitory activity, cognition improving activity, and hepatotoxicity. The pharmacological results indicate that hybrid compounds 1, 2, and 3a potently inhibit cholinesterase in vitro and significantly improve the scopolamine-induced cognition impairment, whereas an analogue (3h) of 2 without the NO donor moiety does not. Compared to tacrine, 1 and 2 show much less hepatotoxicity.

Synthesis and biological evaluation of NO-donor-tacrine hybrids as hepatoprotective anti-Alzheimer drug candidates.

In search of safer anti-Alzheimer drugs, 14 NO-donor-tacrine hybrids (1- 14) were synthesized and evaluated for their ability to inhibit cholinesterases and for vasorelaxation effects. Compounds 1- 13 showed good cholinesterases inhibitory activities in vitro, while 14, particularly, was highly selective, preferring butyrylcholinesterase rather than acetylcholinesterase. Four selected compounds (1, 9, 11, and 14) moderately relaxed the porcine pulmonary arteries in organ bath.

In vivo investigations on the cholinesterase-inhibiting effects of tricyclic quinazolinimines: scopolamine-induced cognitive impairments in rats are attenuated at low dosage and reinforced at higher dosage.

Tricyclic quinazolinimines as a novel class of potent inhibitors of cholinesterases in vitro are micro- and sub-micromolar inhibitors with activities at both acetyl- (AChE) and butyrylcholinesterase (BChE) or at BChE only. To further establish the antiamnesic properties of this class of compounds, an in vivo test system has been established. Cognitive impairment in rats was reversibly induced by scopolamine (0.

Efforts to establish an animal model of Fanconi syndrome after ifosfamide administration to rats.

About 10% of children develop Fanconi syndrome (FS) a few months after ifosfamide (IFO) treatment. To establish an animal model, IFO was injected as 4 or 5 treatment courses (TCs, once daily for 3 consecutive days), to adult female rats (AF, 8 mg 100 g(-1) body wt, 4 TCs), to young female rats (YF, 8 mg 100 g(-1) body wt, 5 TCs) and to male rats (M, 6 mg 100 g(-1) body wt, 4 TCs). In the adult female rats, polyuria with electrolyte and albumin wasting occurred acutely, 2 days after the first treatment course.

Suitability of 5/6 nephrectomy (5/6NX) for the induction of interstitial renal fibrosis in rats--influence of sex, strain, and surgical procedure.

Chronic renal failure (CRF) is a serious clinical problem and currently there are no adequate therapeutic strategies for treatment. Many possible treatment strategies have been tested in rats with CRF induced by subtotal nephrectomy. However, reports in the literature concerning the consequences of this procedure on rat kidney function are contradictory.

Immunocytochemical characterization of the incubated rat renal cortical slices.

The use of renal cortical slices in vitro and the data obtained in these studies have been subjects of controversy, largely due to uncertain viability, e.g., structural and functional integrity of the proximal and other tubules.

Use of gene chip technology for the characterisation of the regulation of renal transport processes and of nephrotoxicity in rats.

Gene expression profiling using microarrays (rat-specific array RG-U34A, Affymetrix, U.S.A.