DEL-FINE: a new tool for assessing the delirogenic properties of drugs of relevance for European pharmacotherapy

This article presents a list of potentially delirogenic properties of drugs that are currently of relevance to drug therapy in Europe, which was created through a Delphi process including experts from professions relevant to diagnosis and treatment of delirium. The Diagnostic and Statistical Manual of Mental Disorders 5 (DSM 5) defines delirium as a disturbance in attention, awareness and cognition that develops over a short period of time and fluctuates. Possible causes of delirium are manifold: usually delirium is considered to develop in a multifactorial way, caused by inalterable parameters, such as advanced age and pre-existing cognitive impairment and precipitated by modifiable parameters, such as the use of certain drugs or substance withdrawal. Delirium is a serious condition with a pronounced impact on morbidity, mortality and costs to the healthcare system. Circumstances and drugs that might precipitate or worsen delirium should therefore be avoided whenever possible. A list of drugs that might have a detrimental influence on the emergence and duration of delirium has been created using the terms “delirogenity” and “delirogenic” to describe the potential of a drug or withdrawal to cause or worsen delirium. The results are novel and noteworthy, as their focus is on substances relevant to European pharmacotherapy. Furthermore, they represent a methodical consensus from a group of experts of a wide variety of professions relevant to the prevention, diagnosis and treatment of delirium, such as nursing, pharmacy, pharmacology, surgical and internal medicine, neurology, psychiatry, intensive care and medicine, with working, teaching and scientific experience in several European countries practicing both in primary and secondary care.     

Delayed onset of odor detection in neonatal mice lacking tenascin-C

The olfactory bulb is one of the few regions in the adult mammalian forebrain in which neurons are constitutively replaced throughout life. New neurons generated in the subventricular zone migrate long distances along the rostral migratory stream to the olfactory bulb where they differentiate into interneurons. Neuronal precursor generation, migration and incorporation into the bulbar network occur in an environment rich in extracellular matrix molecules. We investigated the potential role of one of the constituents of the extracellular matrix, tenascin-C (TNC), in bulbar neurogenesis and olfactory performance using TNC-deficient mice. We found that TNC deficiency resulted in a delayed onset of olfactory responses in neonatal animals. This delay normalized at around postnatal day 10. Interestingly, this delay in early olfactory performance was not due to impaired bulbar neurogenesis as proliferation, migration, incorporation and fate determination of newborn bulbar interneurons were normal in TNC-deficient animals. Thus, we conclude that a constitutive lack of TNC does not affect bulbar neurogenesis, but instead leads to ontogenetically early impairments in olfactory detection.     

Evolution of myelin proteolipid proteins: gene duplication in teleosts and expression pattern divergence

The coevolution of neurons and their supporting glia to the highly specialized axon-myelin unit included the recruitment of proteolipids as neuronal glycoproteins (DMbeta, DMgamma) or myelin proteins (DMalpha/PLP/DM20). Consistent with a genome duplication at the root of teleosts, we identified three proteolipid pairs in zebrafish, termed DMalpha1 and DMalpha2, DMbeta1 and DMbeta2, DMgamma1 and DMgamma2. The paralogous amino acid sequences diverged remarkably after gene duplication, indicating functional specialization. Each proteolipid has adopted a distinct spatio-temporal expression pattern in neural progenitors, neurons, and in glia. DMalpha2, the closest homolog to mammalian PLP/DM20, is coexpressed with P0 in oligodendrocytes and upregulated after optic nerve lesion. DMgamma2 is expressed in multipotential stem cells, and the other four proteolipids are confined to subsets of CNS neurons. Comparing protein sequences and gene structures from birds, teleosts, one urochordate species, and four invertebrates, we have reconstructed major steps in the evolution of proteolipids.     

The Extracellular Matrix Glycoprotein Tenascin-C Is Beneficial for Spinal Cord Regeneration

Tenascin-C (TNC), a major component of the extracellular matrix, is strongly upregulated after injuries of the central nervous system (CNS) but its role in tissue repair is not understood. Both regeneration promoting and inhibiting roles of TNC have been proposed considering its abilities to both support and restrict neurite outgrowth in vitro. Here, we show that spontaneous recovery of locomotor functions after spinal cord injury is impaired in adult TNC-deficient (TNC^–/–) mice in comparison to wild-type (TNC^+/+) mice. The impaired recovery was associated with attenuated excitability of the plantar Hoffmann reflex (H-reflex), reduced glutamatergic input, reduced sprouting of monaminergic axons in the lumbar spinal cord and enhanced post-traumatic degeneration of corticospinal axons. The degeneration of corticospinal axons in TNC^–/– mice was normalized to TNC^+/+ levels by application of the alternatively spliced TNC fibronectin type III homologous domain D (fnD). Finally, overexpression of TNC-fnD via adeno-associated virus in wild-type mice improved locomotor recovery, increased monaminergic axons sprouting, and reduced lesion scar volume after spinal cord injury. The functional efficacy of the viral-mediated TNC indicates a potentially useful approach for treatment of spinal cord injury.     

Evidence for Cis Interaction and Cooperative Signalling by the Heat-stable Antigen Nectadrin (murine CD24) and the Cell Adhesion Molecule L1 in Neurons

L1 is a transmembranal hornophilic cell adhesion molecule of the immunoglobulin superfamily expressed by neural and lymphoid cells. The heat-stable antigen (HSA, murine CD24) nectadrin is a highly and heterogeneously glycosylated glycophosphatidylinositol-linked differentiation antigen of haematopoietic and neural cells. L1 and nectadrin have been shown to mediate cell adhesion and intracellular Ca²⁺ signals in neurons and B lymphoblasts, respectively. Here we show that nectadrin is co-expressed with L1 in murine cerebellar granule cell neurons and neuroblastoma N2A cells. Purified nectadrin bound to L1 with an apparent binding ratio of five nectadrin molecules to one L1 molecule at saturation. Binding between nectadrin and purified N-CAM was not observed. In co-capping experiments nectadrin co-redistributed with L1 and N-CAM. Since in these cells N-CAM and L1 cohere by cis binding nectadrin appears to join the L1-N-CAM complex through binding to L1. Antibodies to each L1 and nectadrin evoked small increases in the intracellular Ca²⁺ concentration. However, when both antibodies were added together or in tandem to the cells, a strong intracellular Ca²⁺ signal was measured that was at least 6- and 10-fold stronger than the signal separately induced by L1 and nectadrin antibodies respectively. Such a cooperative effect was not observed in B lymphoblasts, using the same antibodies, or in neurons, using a combination of L1 and Thy-1 antibodies. Both the weak Ca²⁺ signal mediated by L1 alone and the enhanced signal jointly triggered by antibodies to L1 and nectadrin were inhibited by phorbol 12-myristate 13-acetate and were not significantly affected by Ni²⁺ and Cd²⁺ cations, suggesting that they are related to one another and involve recruitment of intracellular Ca²⁺. Nectadrin therefore appears to join a functional complex of neuronal adhesion molecules and to potentiate the signal transduction pathway of L1, possibly in response to neuron-neuron contact formation.     

Assignment ofAmog (adhesion molecule on glia) gene to mouse chromosome 11 nearZfp-3 andAsgr-1,2 and to human chromosome 17

AMOG, identified as an adhesion molecule that mediates neuron-astrocyte interaction, has structural similarity to the -subunit of Na,K ATPase. We have mapped the AMOG gene to human chromosome 17 and mouse chromosome 11 by somatic cell hybrid analysis. Recombinant inbred strain mapping has placed theAmog locus close to genes for zinc finger protein-3 and the asialoglycoprotein receptor in a region of mouse chromosome 11 that is homologous to human 17p.     

Two Monoclonal Antibodies Recognizing Carbohydrate Epitopes on Neural Adhesion Molecules Interfere with Cell Interactions

We have studied two monoclonal antibodies raised against crude fractions of membrane glycoproteins from adult mouse brain and found them to react with two carbohydrate epitopes expressed on several neural cell adhesion molecules. Other identified and unidentified glycoproteins from different cell types, organs and species were also recognized by these antibodies. Both epitopes are N-glycosidically linked mannosidic or hybrid type oligosaccharides and co-expressed on all the glycoproteins so far tested. In spite of their remarkable similarities, the glycan epitopes are different as shown by ELISA competition assays. In microexplant outgrowth and cell adhesion assays, both antibodies interfere with neural cell adhesion, migration, and neurite outgrowth. These observations, together with previous studies on the L2/HNK-1 glycan (Künemund et al., 1988), indicate that adhesion molecules carry various carbohydrate epitopes mediating different cell interactions in in vitro assays.     

Tenascin-C is involved in motor axon outgrowth in the trunk of developing zebrafish.

Motor axons in the trunk of the developing zebrafish exit from the ventral spinal cord in one ventral root per hemisegment and grow on a common path toward the region of the horizontal myoseptum, where they select their specific pathways. Tenascin-C, a component of the extracellular matrix, is concentrated in this choice region. Adaxial cells and other myotomal cells express tenascin-C mRNA, suggesting that these cells are the source of tenascin-C protein. Overexpressing an axon repellent fragment containing the cysteine-rich region and the epidermal growth factor-like repeats of tenascin-C led to retarded growth of ventral motor nerves between their spinal exit point and the horizontal myoseptum. Injection of a protein fragment containing the same part of tenascin-C also induced slower growth of motor nerves. Conversely, knock down of tenascin-C protein resulted in abnormal lateral branching of ventral motor nerves. In the zebrafish unplugged mutant, in which axons display pathfinding defects in the region of the horizontal myoseptum, tenascin-C immunoreactivity was not detectable in this region, indicating an abnormal extracellular matrix in unplugged. We conclude that tenascin-C is part of a specialized extracellular matrix in the region of the horizontal myoseptum that influences the growth of motor axons.