SHP-1-mediated dephosphorylation of protein tyrosine residues is central to the regulation of several cell signaling pathways, the specificity of which is dictated by the intrinsic affinity of SH2 domains for the flanking sequences of phosphotyrosine residues. By using a modified yeast two-hybrid system and SHP-1 as bait, we have cloned a human cDNA, PILR␣, encoding a 303-amino acid immunoglobulin-like transmembrane receptor bearing two cytoplasmic tyrosines positioned within an immunoreceptor tyrosine-based inhibitory motif. Substrate trapping in combination with pervanadate treatment of 293T cells confirms that PILR␣ associates with SHP-1 in vivo upon tyrosine phosphorylation. Mutation of the tyrosine residues in PILR␣ indicates the pivotal role of the Tyr-269 residue in recruiting SHP-1. Surface plasmon resonance analysis further suggests that the association between PILR␣-Tyr-269 and SHP-1 is mediated primarily via the amino-terminal SH2 domain of the latter. Polymerase chain reaction amplification of cDNA in combination with genomic sequence analysis revealed a second gene, PILR␤, coding for a putative activating receptor as suggested by a truncated cytoplasmic tail and a charged lysine residue in its transmembrane region. The PILR␣ and PILR␤ genes are localized to chromosome 7 which is in contrast with the mapping of known members of the inhibitory receptor superfamily.

ObjectiveTo determine if antidepressant drug usage is associated with cognitive impairment or dementia, including Alzheimer disease (AD).MethodWe conducted a systematic search of Medline, PubMed, PsycINFO, Web of Science, Embase, CINAHL, and the Cochrane Library. An initial screen by abstracts and titles was performed, and relevant full articles were then reviewed and assessed for their methodologic quality. Crude effect estimates were extracted from the included articles and a pooled estimate was obtained using a random effects model.ResultsFive articles were selected from an initial pool of 4,123 articles. Use of antidepressant drugs was associated with a significant twofold increase in the odds of some form of cognitive impairment or dementia (OR = 2.17). Age was identified as a likely modifier of the association between antidepressant use and some form of cognitive impairment or AD/dementia. Studies that included participants with an average age equal to or greater than 65 years showed an increased odds of some form of cognitive impairment with antidepressant drug usage (OR = 1.65), whereas those with participants less than age 65 revealed an even stronger association (OR = 3.25).ConclusionsAntidepressant drug usage is associated with AD/dementia and this is particularly evident if usage begins before age 65. This association may arise due to confounding by depression or depression severity. However, biological mechanisms potentially linking antidepressant exposure to dementia have been described, so an etiological effect of antidepressants is possible. With this confirmation that an association exists, clarification of underlying etiologic pathways requires urgent attention.

Neuroanatomical studies suggest that neuronal atrophy and destruction occur over the course of many years in neurodegenerative conditions such as schizophrenia and Alzheimer's disease. In schizophrenia, early intervention with atypical neuroleptics such as olanzapine has been shown to prevent development of some of the more serious and debilitating symptoms in many patients. The mechanisms whereby olanzapine slows or prevents symptom progression in schizophrenia remain unclear. A previous study found that olanzapine increased mRNA for the copper/zinc isoform of the superoxide dismutase enzyme (SOD-1). We investigated the effects of olanzapine in PC12 cells exposed to hydrogen peroxide. We measured cell viability, observed evidence of necrosis and apoptosis, checked the SOD-1 mRNA by Northern blot analyses, and determined SOD-1 enzyme activity. We found that: (1) the decrease in cell viability induced by hydrogen peroxide was attenuated in PC12 cells pretreated with olanzapine; (2) olanzapine increased SOD enzyme activity in PC12 cells; (3) inhibiting SOD activity with diethyldithiocarbamic acid prevented the cytoprotective actions of olanzapine; and (4) the decrease in SOD-1 mRNA level induced by hydrogen peroxide was blocked by pretreatment with olanzapine. These data indicate that the neuroprotective action of olanzapine includes the upregulation of SOD.

Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of both acute and chronic liver disease. Several hypotheses have emerged following the development of appropriate animal models of HE and following studies using postmortem brain tissue from HE patients. It was originally suggested that primary energy failure was responsible for HE; however, there is now mounting evidence that the pathogenetic defect involves neurotransmission failure. Specific neurotransmitter systems implicated in the pathogenesis of portal-systemic encephalopathy (PSE) include the excitatory amino acid glutamate as well as neuroactive and/or neurotoxic biogenic amine metabolites. Although it has been proposed that alterations in the gamma-aminobutyric acid (GABA) system may play a pathogenic role in HE associated with both chronic and acute liver failure, there is now overwhelming evidence to the contrary. On the other hand, there is evidence to suggest that a subgroup of patients with HE have increased blood and CSF concentrations of substances that bind to GABA-related benzodiazepine receptors in brain. Alterations of both the glutamatergic and serotoninergic neurotransmitter systems in PSE likely result from the metabolic consequences of chronic exposure of brain to toxic levels of ammonia. In addition to its effects on glutamatergic and serotoninergic systems during chronic liver disease, ammonia has been intimately associated with the brain edema invariably observed in acute liver failure. It is evident that, regardless of the type of liver failure, effective reductions of ammonia levels remains the strategy of choice in the prevention of encephalopathy. The further elucidation of neurotransmitter alterations in HE could result in novel "downstream" neuropharmacologic approaches to its prevention and treatment.