_:b555739781 . . . _:b32373239 "Netrins are secreted mediators that exert multiple trophic actions including axon guidance [70], synaptic plasticity [71], prevention of apoptosis [>>72<<,73], adult neurogenesis including in the course of CNS regeneration [74-76], which is believed to be impaired in neuroAIDS [77], and synaptic trophism [54]." . . . . _:b555739788 . . . _:b32373241 . _:b555739793 . _:b32373232 . . _:b555739775 . . _:b32373288 "Release of HIV proteins and cytokine/chemokines from monocytes/macrophages into the CNS parenchyma plays a central role in HIV-associated neurological disorders [11,>>12<<]. Several HIV-1 proteins also possess neurotoxic potential including gp41, Vpr, Nef, Rev and Vpu [13-16]." . . . _:b32373283 . . _:b555739778 . _:b555739739 . _:b32373186 "results" . . _:b32373279 . _:b32373295 . _:b555739779 . _:b32373241 "Netrins are secreted mediators that exert multiple trophic actions including axon guidance [70], synaptic plasticity [71], prevention of apoptosis [72,73], adult neurogenesis including in the course of CNS regeneration [>>74<<-76], which is believed to be impaired in neuroAIDS [77], and synaptic trophism [54]." . _:b555739721 . _:b32373228 . . _:b32373194 . _:b32373221 "also observed in patients with HIVE in the The National NeuroAIDS Tissue Consortium Brain Gene Array [50] and in another study [43], consistent with the notion that HAND in the cART setting correlates with synaptodendritic injury [17,>>18<<]. Dysregulations of genes related to Parkinson\u2019s disease and Huntington\u2019s disease and mitochondrial function, is consistent with previous studies suggesting mitochondrial dysfunction and oxidative stress as potential contributors to HAND" . . . _:b32373219 "Decreased expression of synaptic plasticity and axon guidance genes was also observed in patients with HIVE in the The National NeuroAIDS Tissue Consortium Brain Gene Array [50] and in another study [>>43<<], consistent with the notion that HAND in the cART setting correlates with synaptodendritic injury [17,18]." . _:b555739763 . _:b32373233 . _:b32373242 . . _:b555739869 . . _:b32373252 . _:b32373298 . _:b32373253 . _:b32373254 . _:b32373216 "Col1A2 has been associated with neuroAIDS in humans [>>43<<]. Collagen induction in the CNS has been also observed in brain injury, Alzheimer\u2019s disease, temporal lobe epilepsy, and multiple sclerosis plaques [47-49]." . . _:b32373255 . _:b32373274 . . _:b32373248 . . _:b32373249 . _:b32373226 "IGF signaling has been implicated in synaptic trophism, depression and Parkinson\u2019s disease [>>55<<-57]. GSEA highlighted differential expression of IGF signaling genes including increased Igfbp2 and Igfbp6 expression, which were also found to be increased in the CSF of HIV-1 patients [41]." . _:b32373250 . _:b32373251 . _:b32373267 "neuropathogenesis is also indicated by increased expression of the prostaglandin synthetic enzyme COX-2, which is also a characteristic of other degenerative conditions such as Alzheimer's disease and amyotrophic lateral sclerosis [>>107<<,108]. Dysregulation of prostaglandin synthesis in HAND lends support to the use of inhibitors of cyclooxygenase-2 (COX-2) as well as newer compounds targeting the PGD2 receptor." . _:b32373260 . _:b555739748 . _:b32373299 . _:b32373261 . _:b555739810 . _:b32373262 . . _:b32373263 . _:b32373256 . . _:b32373271 . _:b32373257 . . _:b32373258 . _:b32373285 . _:b32373259 . _:b555739722 . _:b32373268 . . _:b555739790 . _:b32373227 "GSEA highlighted differential expression of IGF signaling genes including increased Igfbp2 and Igfbp6 expression, which were also found to be increased in the CSF of HIV-1 patients [>>41<<]. The IGFBPs have high affinities for the IGFs [58,59] and their increased expression may result in reduced trophic support as well as inflammatory processes [60-62]. The IGF activated gene TDAG51/PHLDA1 [63], which is expressed in both" . _:b32373269 . _:b32373277 . _:b32373270 . _:b555739751 . _:b32373271 . _:b32373293 "The HIV-1 transgenic (Tg) rats used in the present study harbor a gag/pol-deleted HIV-1 provirus under the LTR promoter [>>22<<], resulting in the co-expression of multiple HIV-1 proteins in disease-relevant central nervous system (CNS) cells such as microglia and astrocytes, but not in neurons [22,23]." . _:b32373226 . _:b32373264 . . _:b555739807 . _:b32373265 . _:b32373266 . _:b32373272 "IGF-1 therapy has shown potential in models of both Parkinson\u2019s disease [110,>>111<<] and Alzheimer's disease [112,113]. These effects are at least in part mediated by recruitment of PI3K [111,114]." . _:b32373267 . . _:b32373276 . _:b32373277 . _:b32373278 . _:b555739862 . . _:b32373279 . _:b555739863 . _:b32373294 . _:b32373272 . _:b32373273 . _:b32373284 "background" . _:b32373274 . _:b32373293 . _:b32373275 . . . _:b32373252 "Peroxisome dysfunction may also contribute to increased lipid peroxidation and cellular aging in HIV-1 [>>90<<,91]. In apparent agreement with the dysregulation of these pathways, evidence suggestive of altered phospholipid metabolism has been reported in HIV-1 patients [92,93] and peroxisome dysregulation can be indicative of altered brain" . _:b32373200 _:b32373280 . _:b32373284 . _:b555739838 . _:b32373200 _:b32373281 . _:b32373200 _:b32373282 . . _:b32373200 _:b32373283 . _:b32373213 "Prostaglandins have been implicated in inflammation-induced working memory deficits [44] and imaging evidence supports that brain arachidonic acid metabolism in HIV-1 transgenic rats is upregulated [>>45<<]. PGD2 has been implicated in the induction of astrogliosis and demyelination [42,46] and has been associated with immune activation, astrogliosis, microgliosis, and neuroAIDS in humans [42]. Col1A2 has been associated with neuroAIDS in" . _:b32373285 . _:b32373286 . _:b555739808 . _:b32373287 . _:b32373209 . _:b32373199 . _:b32373280 . _:b32373281 . _:b555739850 . _:b32373282 . _:b32373283 . _:b32373200 _:b32373252 . _:b32373200 _:b32373253 . _:b555739773 . _:b32373200 _:b32373254 . _:b32373200 _:b32373255 . _:b32373292 . _:b32373200 _:b32373248 . . _:b32373200 _:b32373249 . _:b32373200 _:b32373250 . _:b32373255 . _:b32373200 _:b32373251 . . _:b32373293 . _:b32373200 _:b32373260 . _:b32373200 _:b32373261 . _:b32373200 _:b32373262 . _:b32373301 . _:b32373277 "Additionally, chronic treatment with IGF-1 was protective in vitro against gp120-mediated neuronal damage and was synergistic with erythropoietin (EPO), at least in part, through cooperative activation of PI3K [>>115<<]. GLP-1 and GLP-1 analogs, which activate partially overlapping signal transduction pathways as insulin and IGF-1 [114], have also shown beneficial effects in preclinical models of neurodegenerative disorders [116-119]. There is currently" . _:b32373200 _:b32373263 . _:b32373294 . _:b32373200 _:b32373256 . _:b32373200 _:b32373257 . _:b32373200 _:b32373258 . _:b32373200 _:b32373259 . _:b32373295 . _:b32373200 _:b32373268 . . _:b32373200 _:b32373269 . _:b32373200 _:b32373270 . _:b32373200 _:b32373271 . _:b32373288 . _:b32373200 _:b32373264 . _:b32373200 _:b32373265 . _:b32373200 _:b32373266 . _:b32373200 _:b32373267 . _:b32373289 . _:b32373200 _:b32373276 . _:b32373200 _:b32373277 . _:b32373200 _:b32373278 . _:b32373200 _:b32373279 . _:b32373290 . _:b32373200 _:b32373272 . _:b32373200 _:b32373273 . . _:b32373200 _:b32373274 . _:b32373200 _:b32373275 . _:b32373291 . . _:b32373284 . _:b32373300 . . _:b32373227 . _:b32373301 . _:b555739770 . _:b32373289 "Several HIV-1 proteins also possess neurotoxic potential including gp41, Vpr, Nef, Rev and Vpu [>>13<<-16]. Evidence suggests that the toxic actions of low levels of HIV-1 products are key in the neuropathogenesis of persistent central nervous system HIV disease in the setting of cART. In fact, after the introduction of cART, HAND do not" . _:b32373296 . . _:b32373297 . _:b555739846 . _:b32373298 . _:b32373299 . _:b32373289 . . . . . _:b32373247 . . _:b555739715 . _:b555739761 . _:b555739718 . . . . . . . _:b32373237 "Netrins are secreted mediators that exert multiple trophic actions including axon guidance [>>70<<], synaptic plasticity [71], prevention of apoptosis [72,73], adult neurogenesis including in the course of CNS regeneration [74-76], which is believed to be impaired in neuroAIDS [77], and synaptic trophism [54]." . . _:b32373202 "In this regard it should be noted that spontaneous alternation behavior (SAB) has been used in aged rats with visual impairments [34] and to compare anophthalmic mutant mice to wild-type controls [>>35<<]. It has been previously shown that HIV transgenic rats exhibit impairment in a spatial reversal learning task [36] without any deficit in spatial memory or motor activity [37]. Our results extend these studies by showing that HIV rats" . _:b32373284 _:b32373300 . _:b32373284 _:b32373301 . _:b555739789 . _:b555739717 . _:b32373284 _:b32373296 . _:b32373284 _:b32373297 . _:b32373284 _:b32373298 . _:b555739716 . _:b32373284 _:b32373299 . _:b32373203 "It has been previously shown that HIV transgenic rats exhibit impairment in a spatial reversal learning task [>>36<<] without any deficit in spatial memory or motor activity [37]." . _:b555739719 . _:b555739718 . . _:b32373284 _:b32373285 . _:b32373284 _:b32373286 . _:b555739713 . _:b32373284 _:b32373287 . _:b555739712 . _:b32373284 _:b32373292 . _:b32373284 _:b32373293 . _:b32373284 _:b32373294 . _:b555739715 . _:b32373284 _:b32373295 . _:b32373228 "The IGFBPs have high affinities for the IGFs [58,>>59<<] and their increased expression may result in reduced trophic support as well as inflammatory processes [60-62]." . _:b32373284 _:b32373288 . _:b32373284 _:b32373289 . _:b32373284 _:b32373290 . _:b555739714 . _:b32373284 _:b32373291 . _:b555739725 . _:b555739827 . . . _:b555739724 . _:b32373266 . _:b555739800 . _:b555739727 . _:b555739822 . _:b555739726 . _:b555739721 . _:b555739720 . _:b555739732 . . _:b32373215 "PGD2 has been implicated in the induction of astrogliosis and demyelination [42,46] and has been associated with immune activation, astrogliosis, microgliosis, and neuroAIDS in humans [>>42<<]. Col1A2 has been associated with neuroAIDS in humans [43]. Collagen induction in the CNS has been also observed in brain injury, Alzheimer\u2019s disease, temporal lobe epilepsy, and multiple sclerosis plaques [47-49]." . _:b555739752 . . _:b555739723 . . _:b555739722 . _:b555739855 . _:b32373231 . _:b555739733 . . _:b555739732 . . _:b555739864 . _:b555739735 . . . _:b555739734 . _:b555739729 . _:b555739728 . _:b555739731 . _:b32373233 . . _:b555739730 . _:b555739741 . . _:b555739762 . _:b555739740 . . _:b32373193 . . _:b555739743 . . _:b32373247 "The PI3K-mTOR signaling pathway is involved in synaptic plasticity [>>84<<-86] and was shown to be dysregulated in the frontal cortex of patients with neuroAIDS [43]." . _:b555739742 . _:b555739837 . _:b32373195 . . _:b555739737 . _:b555739726 . _:b555739736 . _:b32373244 "The GSEA analysis highlights a substantial downregulation of intracellular signaling pathways relevant to trophic support such as the PI3K-mTOR signaling pathway, which mediates a vast array of trophic signals [>>78<<]; the LKB1 pathway, which is key to neuronal survival following mitochondrial insults [79] and cross-talks with the PI3K-mTOR pathway; and the ILK pathway, which is involved in mediating trophic signals of the extracellular matrix and" . _:b555739739 . . _:b555739738 . . _:b32373255 "In apparent agreement with the dysregulation of these pathways, evidence suggestive of altered phospholipid metabolism has been reported in HIV-1 patients [92,>>93<<] and peroxisome dysregulation can be indicative of altered brain oxidative balance associated with HIV-1 [94]." . _:b555739749 . _:b555739748 . _:b32373214 "PGD2 has been implicated in the induction of astrogliosis and demyelination [>>42<<,46] and has been associated with immune activation, astrogliosis, microgliosis, and neuroAIDS in humans [42]." . _:b555739751 . . _:b32373246 "insults [79] and cross-talks with the PI3K-mTOR pathway; and the ILK pathway, which is involved in mediating trophic signals of the extracellular matrix and trophic factors as well as in the anti-apoptotic effect of the PI3K pathway [>>80<<]. Recent studies have indicated impaired processing and transport of neurotrophic factors in HIV-1 neuropathogenesis [81-83]." . _:b32373241 . . _:b555739750 . _:b555739737 . _:b555739745 . _:b555739801 . _:b555739744 . _:b555739853 . _:b555739842 . _:b555739747 . _:b555739746 . . . _:b555739799 . . _:b555739757 . _:b32373240 "Netrins are secreted mediators that exert multiple trophic actions including axon guidance [70], synaptic plasticity [71], prevention of apoptosis [72,>>73<<], adult neurogenesis including in the course of CNS regeneration [74-76], which is believed to be impaired in neuroAIDS [77], and synaptic trophism [54]." . _:b555739756 . _:b555739759 . _:b555739758 . _:b555739753 . _:b555739768 . _:b32373243 "including axon guidance [70], synaptic plasticity [71], prevention of apoptosis [72,73], adult neurogenesis including in the course of CNS regeneration [74-76], which is believed to be impaired in neuroAIDS [77], and synaptic trophism [>>54<<]." . _:b555739752 . . _:b555739755 . . _:b555739754 . _:b555739755 . _:b555739765 . . _:b32373253 "Peroxisome dysfunction may also contribute to increased lipid peroxidation and cellular aging in HIV-1 [90,>>91<<]. In apparent agreement with the dysregulation of these pathways, evidence suggestive of altered phospholipid metabolism has been reported in HIV-1 patients [92,93] and peroxisome dysregulation can be indicative of altered brain oxidative" . . _:b555739764 . . _:b32373273 . _:b555739767 . _:b555739783 . _:b555739877 . _:b555739766 . _:b32373192 "Briefly as previously described [>>124<<] saggital brain vibratome sections from the non-Tg and HIV-1 Tg rats were incubated overnight at 4\u00B0C with the rabbit polyclonal antibodies against Tat (NIH AIDS reagent program; cat# 1974) or mouse monoclonal antibodies against the" . _:b555739713 . _:b555739761 . _:b32373223 . _:b555739760 . _:b555739848 . . _:b555739763 . _:b555739762 . . . _:b32373248 . _:b555739773 . _:b555739772 . _:b32373259 . _:b555739734 . _:b555739775 . _:b555739746 . _:b555739774 . . _:b555739769 . _:b555739833 . _:b32373233 "The IGF activated gene TDAG51/PHLDA1 [63], which is expressed in both neurons and glial cells [64], is implicated in insulin signaling [65] and has been shown to have differential effects on susceptibility to apoptosis [>>66<<-68]." . _:b555739768 . _:b32373217 "Collagen induction in the CNS has been also observed in brain injury, Alzheimer\u2019s disease, temporal lobe epilepsy, and multiple sclerosis plaques [>>47<<-49]." . _:b555739771 . _:b555739770 . _:b32373276 "These effects are at least in part mediated by recruitment of PI3K [111,>>114<<]. Additionally, chronic treatment with IGF-1 was protective in vitro against gp120-mediated neuronal damage and was synergistic with erythropoietin (EPO), at least in part, through cooperative activation of PI3K [115]." . _:b555739781 . _:b555739777 . _:b32373229 . . _:b555739780 . _:b32373286 . _:b555739783 . _:b32373198 . . _:b555739782 . _:b555739777 . _:b555739776 . _:b555739825 . _:b555739779 . _:b555739784 . _:b32373220 "was also observed in patients with HIVE in the The National NeuroAIDS Tissue Consortium Brain Gene Array [50] and in another study [43], consistent with the notion that HAND in the cART setting correlates with synaptodendritic injury [>>17<<,18]. Dysregulations of genes related to Parkinson\u2019s disease and Huntington\u2019s disease and mitochondrial function, is consistent with previous studies suggesting mitochondrial dysfunction and oxidative stress as potential contributors to" . . _:b555739795 . _:b555739778 . _:b555739861 . _:b32373203 . _:b555739789 . . _:b32373243 . _:b32373301 "We used the Gene Set Enrichment Analysis (GSEA) algorithm [>>28<<] to identify molecular pathways that are differentially activated in HIV-1 Tg rats." . _:b32373239 . _:b555739788 . _:b32373189 . _:b32373249 "Downregulated genesets also contain numerous MAP kinases including ERK1 (MAPK3), which was previously implicated in the neurological actions of HIV-1 products [>>87<<]." . _:b555739791 . _:b32373190 . _:b32373206 . _:b555739790 . . _:b555739785 . _:b555739858 . _:b32373229 "The IGFBPs have high affinities for the IGFs [58,59] and their increased expression may result in reduced trophic support as well as inflammatory processes [>>60<<-62]. The IGF activated gene TDAG51/PHLDA1 [63], which is expressed in both neurons and glial cells [64], is implicated in insulin signaling [65] and has been shown to have differential effects on susceptibility to apoptosis [66-68]." . . _:b555739784 . _:b555739787 . _:b555739786 . _:b555739797 . _:b555739796 . _:b555739799 . _:b555739798 . _:b32373286 . _:b555739793 . _:b555739792 . _:b555739795 . _:b555739794 . _:b555739725 . _:b555739805 . _:b555739804 . _:b555739807 . _:b555739806 . . _:b555739820 . _:b555739801 . _:b32373283 "However, as PI3K appears to play a role in the regulation of the HIV-1 LTR promoter and virus latency [122,>>123<<], activation of PI3K in the cells that harbor the provirus may increase levels of expression of HIV-1 products, potentially leading to detrimental effects on cognition." . _:b555739800 . . _:b555739803 . . . _:b555739813 . _:b555739794 . _:b555739742 . _:b555739802 . _:b32373206 "ISG-15 was proposed to be a predictive biomarker for HAND [>>39<<,40]. In particular, ISG-15 was shown to correlate with neuropathology and viral load and ISG-15 CSF levels may be predictive of future neurocognitive impairments [38]." . _:b555739813 . . _:b32373261 "Memantine and nimodipine are intended to protect from excitotoxic neuronal damage associated with excessive glutamate release [>>102<<,103]. Selegiline is a drug used for the treatment of early-stage Parkinson\u2019s disease, depression and dementia [104,105]." . . _:b555739812 . . _:b555739815 . _:b555739872 . _:b555739873 . _:b555739843 . _:b555739874 . _:b555739875 . _:b555739814 . _:b555739876 . _:b555739877 . _:b555739809 . _:b555739808 . . _:b555739776 . _:b555739811 . _:b32373207 "ISG-15 was proposed to be a predictive biomarker for HAND [39,>>40<<]. In particular, ISG-15 was shown to correlate with neuropathology and viral load and ISG-15 CSF levels may be predictive of future neurocognitive impairments [38]." . _:b555739856 . . _:b555739857 . _:b555739858 . _:b555739859 . _:b555739810 . _:b555739860 . _:b555739861 . _:b555739717 . _:b555739862 . . _:b555739863 . _:b555739821 . _:b555739864 . _:b555739815 . _:b555739865 . _:b555739866 . _:b555739817 . _:b555739867 . . _:b555739868 . _:b555739820 . _:b555739869 . _:b555739870 . . . _:b555739871 . _:b555739823 . _:b555739840 . _:b555739841 . _:b555739842 . _:b555739843 . _:b555739822 . _:b555739844 . _:b32373226 . _:b555739845 . _:b555739846 . _:b555739847 . _:b555739817 . _:b555739848 . _:b555739834 . _:b555739792 . _:b555739849 . _:b555739850 . _:b32373280 "There is currently great interest in developing drugs to modulate NRG1\u2013ErbB4 and netrin signalling [>>120<<,121]. Netrin agonists may be potentially beneficial in neuroAIDS both by exerting neurotrophic actions and by reducing inflammation [120]. The PI3K pathway is itself a potential target for reversal of the synaptodendritic injury" . _:b555739851 . _:b555739816 . _:b555739852 . _:b555739853 . _:b555739854 . _:b555739855 . _:b555739819 . _:b555739824 . _:b32373223 . _:b32373248 "The PI3K-mTOR signaling pathway is involved in synaptic plasticity [84-86] and was shown to be dysregulated in the frontal cortex of patients with neuroAIDS [>>43<<]. Downregulated genesets also contain numerous MAP kinases including ERK1 (MAPK3), which was previously implicated in the neurological actions of HIV-1 products [87]." . _:b555739825 . _:b32373187 . _:b555739826 . . _:b555739827 . _:b555739818 . _:b555739828 . _:b555739749 . . _:b555739829 . _:b555739830 . _:b555739831 . _:b555739829 . _:b555739832 . _:b555739833 . _:b555739834 . _:b555739769 . _:b555739835 . _:b555739828 . _:b555739836 . _:b555739837 . _:b32373285 . _:b555739838 . _:b32373188 . _:b555739839 . _:b32373222 . _:b555739808 . _:b555739831 . _:b555739809 . _:b555739810 . _:b555739811 . _:b32373269 . _:b32373218 "Decreased expression of synaptic plasticity and axon guidance genes was also observed in patients with HIVE in the The National NeuroAIDS Tissue Consortium Brain Gene Array [>>50<<] and in another study [43], consistent with the notion that HAND in the cART setting correlates with synaptodendritic injury [17,18]." . _:b555739812 . _:b555739830 . _:b555739813 . _:b555739814 . _:b555739815 . _:b555739825 . _:b555739816 . _:b555739817 . _:b555739818 . _:b555739819 . _:b555739796 . _:b555739824 . _:b555739820 . _:b555739821 . _:b555739714 . _:b555739822 . . _:b555739823 . _:b555739827 . _:b555739792 . _:b32373238 "Netrins are secreted mediators that exert multiple trophic actions including axon guidance [70], synaptic plasticity [>>71<<], prevention of apoptosis [72,73], adult neurogenesis including in the course of CNS regeneration [74-76], which is believed to be impaired in neuroAIDS [77], and synaptic trophism [54]." . _:b555739793 . _:b555739794 . _:b555739795 . _:b555739826 . _:b555739796 . _:b555739797 . _:b555739798 . _:b555739799 . _:b32373208 "In particular, ISG-15 was shown to correlate with neuropathology and viral load and ISG-15 CSF levels may be predictive of future neurocognitive impairments [>>38<<]. Several other inflammation-related genes induced in the hippocampus of HIV-1 Tg rats were previously associated with neuroAIDS in humans including IGF binding proteins [41], prostaglandin D2 (PGD2) synthase [42], and the pro-alpha2" . . _:b555739800 . _:b555739837 . _:b555739801 . _:b32373265 . _:b555739802 . . _:b555739803 . _:b555739836 . _:b555739804 . _:b555739805 . _:b555739766 . _:b555739806 . _:b555739807 . _:b555739839 . _:b555739776 . _:b555739777 . _:b555739778 . _:b555739779 . _:b32373270 "expression results as well as the previous literature also point to a role in HAND of several signaling systems with the potential to provide trophic support to synapses and reverse the synaptodendritic injury associated with HAND [17,>>18<<]. Among them are IGF, ErbB and netrin signaling and the PI3K-mTOR signal transduction pathway, which mediates trophic and plastic actions of various signaling systems." . _:b555739838 . _:b555739780 . _:b555739781 . _:b555739782 . . _:b555739783 . _:b555739833 . _:b32373264 . _:b555739784 . . _:b555739809 . _:b555739785 . _:b555739786 . _:b555739787 . . _:b555739832 . _:b555739788 . _:b32373188 "The Gene Set Enrichment Analysis (GSEA) algorithm was used for pathway analysis using the MSigDB C2 canonical pathway collection [>>28<<]. Of the significantly differentially regulated pathways with statistical significance of p\u2009\u2264\u20090.01, 8 showed increased activation, while the rest was decreased. Among the increased ones are pathways consistent with astrocyte and microglia" . _:b555739789 . _:b555739790 . _:b555739791 . _:b32373279 "GLP-1 and GLP-1 analogs, which activate partially overlapping signal transduction pathways as insulin and IGF-1 [114], have also shown beneficial effects in preclinical models of neurodegenerative disorders [>>116<<-119]. There is currently great interest in developing drugs to modulate NRG1\u2013ErbB4 and netrin signalling [120,121]. Netrin agonists may be potentially beneficial in neuroAIDS both by exerting neurotrophic actions and by reducing" . _:b555739835 . _:b555739760 . _:b555739761 . _:b555739762 . _:b555739763 . _:b555739834 . _:b555739764 . _:b555739765 . _:b555739766 . . _:b32373223 . _:b555739767 . _:b555739845 . _:b555739768 . _:b555739769 . _:b555739770 . _:b555739771 . . _:b32373187 "Pathway analysis with the GSEA algorithm [>>28<<] revealed 23 pathways significantly differentially regulated with statistical significance of p\u2009\u2264\u20090.01 (Figures\u00A0 6 and 7, Additional file 3:" . _:b555739772 . _:b555739844 . _:b555739773 . _:b555739774 . _:b555739775 . _:b555739847 . _:b555739744 . _:b32373271 "IGF-1 therapy has shown potential in models of both Parkinson\u2019s disease [>>110<<,111] and Alzheimer's disease [112,113]. These effects are at least in part mediated by recruitment of PI3K [111,114]." . _:b555739745 . . _:b555739746 . _:b555739747 . _:b555739846 . _:b555739748 . _:b555739749 . _:b555739750 . _:b555739751 . _:b555739841 . _:b555739752 . _:b555739753 . . _:b555739754 . _:b555739755 . . _:b555739756 . _:b555739840 . _:b555739765 . _:b555739757 . _:b555739758 . _:b555739759 . _:b555739843 . _:b555739728 . _:b555739729 . _:b555739730 . _:b555739731 . _:b555739842 . _:b555739732 . _:b555739718 "7"^^ . _:b555739733 . _:b555739818 . _:b555739734 . _:b555739735 . _:b555739719 "6"^^ . _:b555739736 . _:b555739853 . _:b555739737 . _:b555739738 . _:b555739739 . _:b555739852 . _:b555739740 . _:b555739741 . _:b555739716 "8"^^ . _:b555739742 . _:b555739743 . _:b555739855 . _:b555739750 . _:b555739712 . _:b555739713 . _:b555739797 . _:b555739717 "8"^^ . _:b555739714 . _:b555739715 . _:b555739854 . _:b32373210 "Several other inflammation-related genes induced in the hippocampus of HIV-1 Tg rats were previously associated with neuroAIDS in humans including IGF binding proteins [41], prostaglandin D2 (PGD2) synthase [>>42<<], and the pro-alpha2 chain of type I collagen, Col1A2 [43]." . _:b555739716 . _:b555739717 . _:b555739718 . _:b555739714 "9"^^ . _:b555739719 . _:b555739849 . _:b555739720 . _:b555739721 . _:b555739722 . _:b555739715 "9"^^ . _:b555739723 . . _:b555739724 . _:b555739848 . _:b555739713 "10"^^ . _:b555739725 . . _:b555739726 . _:b555739727 . _:b555739851 . _:b555739712 "13"^^ . _:b555739850 . _:b555739725 "5"^^ . _:b555739861 . _:b555739724 "5"^^ . _:b555739860 . _:b32373296 . . _:b555739727 "5"^^ . _:b555739863 . _:b555739726 "5"^^ . . _:b555739862 . _:b32373212 . _:b555739857 . _:b555739720 "6"^^ . _:b555739856 . _:b555739723 "5"^^ . _:b555739721 "6"^^ . _:b555739859 . _:b555739756 . _:b555739722 "5"^^ . _:b555739858 . . _:b555739733 "4"^^ . _:b555739869 . _:b555739732 "4"^^ . _:b555739868 . _:b555739735 "4"^^ . _:b32373278 "GLP-1 and GLP-1 analogs, which activate partially overlapping signal transduction pathways as insulin and IGF-1 [>>114<<], have also shown beneficial effects in preclinical models of neurodegenerative disorders [116-119]." . _:b555739871 . _:b555739734 "4"^^ . _:b555739870 . _:b32373269 "gene expression results as well as the previous literature also point to a role in HAND of several signaling systems with the potential to provide trophic support to synapses and reverse the synaptodendritic injury associated with HAND [>>17<<,18]. Among them are IGF, ErbB and netrin signaling and the PI3K-mTOR signal transduction pathway, which mediates trophic and plastic actions of various signaling systems." . _:b555739729 "4"^^ . _:b32373290 . _:b555739865 . _:b555739728 "5"^^ . . _:b555739864 . _:b32373208 . _:b555739731 "4"^^ . _:b555739867 . _:b32373281 "Netrin agonists may be potentially beneficial in neuroAIDS both by exerting neurotrophic actions and by reducing inflammation [>>120<<]. The PI3K pathway is itself a potential target for reversal of the synaptodendritic injury associated with HAND. However, as PI3K appears to play a role in the regulation of the HIV-1 LTR promoter and virus latency [122,123], activation" . _:b555739730 "4"^^ . _:b555739847 . _:b555739866 . _:b555739741 "3"^^ . _:b555739877 . _:b555739740 "3"^^ . . _:b555739876 . _:b555739743 "3"^^ . _:b555739724 . _:b555739744 . _:b555739742 "3"^^ . _:b555739737 "4"^^ . _:b555739873 . _:b555739826 . _:b555739736 "4"^^ . _:b555739872 . _:b32373254 . . _:b555739730 . _:b555739739 "4"^^ . _:b32373232 "The IGF activated gene TDAG51/PHLDA1 [63], which is expressed in both neurons and glial cells [64], is implicated in insulin signaling [>>65<<] and has been shown to have differential effects on susceptibility to apoptosis [66-68]." . _:b555739875 . _:b555739738 "4"^^ . _:b555739874 . . _:b555739749 "3"^^ . _:b32373265 "in HAND and potentially for other therapeutics used in Parkinson's disease such as methylphenidate, a stimulant that reduces reuptake of dopamine and norepinephrine that has proven beneficial in lowering fatigue scores in HIV patients [>>106<<]. The present results of increased PGD2 synthase (Ptgds), is in keeping with previous studies that showed elevated PGD2 levels in HIV-1-positive patients [42]." . . _:b555739782 . _:b555739748 "3"^^ . _:b555739751 "3"^^ . . _:b555739750 "3"^^ . _:b32373205 . . _:b555739745 "3"^^ . . _:b555739744 "3"^^ . _:b555739747 "3"^^ . . . _:b555739746 "3"^^ . _:b32373299 "virus replication and production, HIV-1 Tg rats have a progressive clinical presentation leading to a picture reminiscent of some of AIDS features later in life that includes immunological abnormalities and neurological manifestations [>>22<<,27]." . _:b555739821 . _:b555739757 "3"^^ . _:b555739835 . _:b555739756 "3"^^ . _:b555739759 "3"^^ . _:b555739758 "3"^^ . . _:b32373200 "discussion" . _:b555739753 "3"^^ . . _:b555739836 . _:b555739752 "3"^^ . . . . _:b555739755 "3"^^ . _:b32373225 "Tg rats involve IGF, ErbB and netrin, all of which have been shown to exert trophic actions on dendritic spines [52-55], suggesting that dysregulation of these pathways can contribute to the synaptodendritic injury seen in neuroAIDS [17,>>18<<]." . _:b32373189 "To determine the functional correlates of the present gene expression and pathologic findings, we then investigated working memory in HIV-1 Tg rats using a hippocampus and prefrontal cortex-dependent task [>>29<<-32]. Rats were tested in the dark in spontaneous alternations in the T-Maze, which is a paradigm sensitive to prefrontal cortex and hippocampal impairments [29-32]." . . _:b555739754 "3"^^ . _:b555739765 "3"^^ . _:b555739764 "3"^^ . _:b555739871 . _:b555739767 "3"^^ . _:b32373289 . _:b555739766 "3"^^ . . . _:b555739761 "3"^^ . _:b555739760 "3"^^ . . _:b555739763 "3"^^ . _:b32373260 "This is especially needed in neuroAIDS as no targeted therapy other than cART is currently recommended for the management of HAND [100,>>101<<]. Adjunctive therapies for HAND explored to date include the low-affinity antagonist of the NMDA type glutamate receptor memantine, the calcium channel blocker nimodipine, and the monoamine oxidase B inhibitor selegiline, in addition to" . _:b555739762 "3"^^ . . _:b555739773 "2"^^ . _:b32373217 . _:b555739772 "2"^^ . _:b32373231 "The IGF activated gene TDAG51/PHLDA1 [63], which is expressed in both neurons and glial cells [>>64<<], is implicated in insulin signaling [65] and has been shown to have differential effects on susceptibility to apoptosis [66-68]." . _:b555739775 "2"^^ . _:b555739774 "2"^^ . . _:b555739769 "3"^^ . . _:b555739806 . _:b555739768 "3"^^ . _:b32373190 . _:b32373253 . _:b555739771 "3"^^ . _:b32373189 . _:b555739770 "3"^^ . _:b555739781 "2"^^ . . _:b555739780 "2"^^ . . _:b555739783 "2"^^ . _:b555739859 . _:b555739782 "2"^^ . _:b555739777 "2"^^ . _:b32373292 . _:b32373281 . _:b555739776 "2"^^ . _:b555739828 . _:b32373250 "Peroxisomes and mitochondria exhibit a functional interplay in fatty acid processing and intermediate metabolism [>>88<<,89]. It could be envisioned that if peroxisomal metabolism is slowed, critical metabolic intermediates (e.g., acetyl-CoA) may not be adequately supplied to mitochondria and, conversely, disruption of mitochondrial metabolism can similarly" . _:b555739779 "2"^^ . _:b32373280 . _:b555739778 "2"^^ . _:b555739789 "2"^^ . . _:b555739788 "2"^^ . _:b32373251 "Peroxisomes and mitochondria exhibit a functional interplay in fatty acid processing and intermediate metabolism [88,>>89<<]. It could be envisioned that if peroxisomal metabolism is slowed, critical metabolic intermediates (e.g., acetyl-CoA) may not be adequately supplied to mitochondria and, conversely, disruption of mitochondrial metabolism can similarly" . . . _:b555739873 . _:b555739791 "2"^^ . _:b555739849 . _:b555739790 "2"^^ . _:b555739785 "2"^^ . _:b555739784 "2"^^ . _:b555739787 "2"^^ . _:b555739786 "2"^^ . . _:b32373196 "RT-PCR was carried out as previously described [125,>>127<<,128] with SYBR Green (BioRad) detection using an iQ5 Real-Time PCR Detection System (BioRad, Hercules, CA)." . _:b555739797 "2"^^ . _:b32373186 . _:b32373262 "Memantine and nimodipine are intended to protect from excitotoxic neuronal damage associated with excessive glutamate release [102,>>103<<]. Selegiline is a drug used for the treatment of early-stage Parkinson\u2019s disease, depression and dementia [104,105]." . _:b32373257 . _:b32373230 . _:b555739796 "2"^^ . _:b32373191 . . _:b555739799 "2"^^ . . _:b555739798 "2"^^ . _:b555739798 . _:b32373200 . _:b555739793 "2"^^ . _:b555739792 "2"^^ . . . _:b555739795 "2"^^ . _:b555739794 "2"^^ . _:b555739805 "2"^^ . . _:b555739872 . _:b555739767 . _:b555739804 "2"^^ . _:b555739807 "2"^^ . _:b32373260 . _:b555739806 "2"^^ . _:b555739801 "2"^^ . _:b32373258 "analysis can be a useful tool both to gain insights in the pathogenesis and for the identification of potential new therapeutic targets by identifying the signaling pathways that have the potential to modify the disease pathophysiology [>>97<<-99]. This is especially needed in neuroAIDS as no targeted therapy other than cART is currently recommended for the management of HAND [100,101]." . _:b555739727 . _:b555739800 "2"^^ . _:b555739803 "2"^^ . _:b32373218 . _:b555739802 "2"^^ . . _:b555739813 "2"^^ . _:b555739854 . _:b555739812 "2"^^ . . _:b32373204 "It has been previously shown that HIV transgenic rats exhibit impairment in a spatial reversal learning task [36] without any deficit in spatial memory or motor activity [>>37<<]. Our results extend these studies by showing that HIV rats also exhibit impairment in a working memory task. The deficits in the reversal learning task and the working memory task may both be explained by an impairment in the ability of" . _:b555739815 "2"^^ . _:b555739814 "2"^^ . _:b555739809 "2"^^ . _:b32373249 . . _:b555739808 "2"^^ . _:b32373258 . _:b555739743 . . _:b555739811 "2"^^ . _:b555739810 "2"^^ . _:b32373198 "Rats were first habituated to the experimenters over 4\u00A0days (5\u00A0min/day) as described in [>>29<<] and [30]." . . _:b555739821 "2"^^ . . _:b32373262 . _:b555739820 "2"^^ . _:b555739823 "2"^^ . _:b32373193 "Processing of Affymetrix microarrays was carried out as previously described, according to manufacturer\u2019s procedures [>>125<<,126]. All analyses were performed with R statistical software. We analyzed 11 samples (5 HIV-1 Tg rats; 6 controls) hybridized on Affymetrix Rat 230.2." . _:b555739856 . . _:b555739822 "2"^^ . . . _:b555739817 "2"^^ . _:b555739816 "2"^^ . _:b555739819 "2"^^ . _:b555739866 . _:b555739818 "2"^^ . . _:b555739829 "2"^^ . _:b32373300 . . _:b555739828 "2"^^ . . . _:b555739831 "2"^^ . _:b555739830 "2"^^ . _:b32373285 . . . _:b555739825 "2"^^ . _:b555739831 . . _:b555739824 "2"^^ . _:b32373211 . _:b32373268 "In this regard, a COX-2 inhibitor has shown promise in downregulating immune activation and improving T cell function in HIV-1 patients [>>109<<]." . _:b32373286 "HIV-associated dementia has been associated with an increased prevalence of milder and chronic forms of HIV-associated neurocognitive disorders (HAND) and HIV-associated major depressive disorder along with increased life expectancy [>>4<<-10]." . _:b555739827 "2"^^ . . _:b555739844 . _:b555739826 "2"^^ . _:b555739837 "2"^^ . _:b32373256 "Fbxw11 is the gene coding for \u03B2TrCP, a cellular ubiquitin ligase that was found to be bound by the HIV-1 Vpu viral protein [>>95<<]. Nucleophosmin/B23, encoded by the Npm1 gene, is a nuclear chaperone implicated in the nuclear transport of Tat [96]." . . . _:b555739836 "2"^^ . _:b555739839 "2"^^ . . _:b555739838 "2"^^ . . _:b32373263 . _:b555739833 "2"^^ . _:b555739832 "2"^^ . . . _:b555739835 "2"^^ . _:b555739834 "2"^^ . . _:b555739845 "2"^^ . . _:b555739844 "2"^^ . _:b555739847 "2"^^ . . _:b555739846 "2"^^ . . . . _:b555739841 "2"^^ . "10.1186%2F1750-1326-9-26" . _:b555739840 "2"^^ . _:b555739843 "2"^^ . _:b555739842 "2"^^ . _:b555739758 . _:b555739754 . _:b555739853 "2"^^ . . _:b555739852 "2"^^ . . . _:b555739855 "2"^^ . _:b32373212 "Prostaglandins have been implicated in inflammation-induced working memory deficits [>>44<<] and imaging evidence supports that brain arachidonic acid metabolism in HIV-1 transgenic rats is upregulated [45]." . _:b555739854 "2"^^ . _:b555739849 "2"^^ . _:b555739848 "2"^^ . _:b555739851 "2"^^ . _:b555739850 "2"^^ . _:b555739830 . _:b32373287 "Release of HIV proteins and cytokine/chemokines from monocytes/macrophages into the CNS parenchyma plays a central role in HIV-associated neurological disorders [>>11<<,12]. Several HIV-1 proteins also possess neurotoxic potential including gp41, Vpr, Nef, Rev and Vpu [13-16]." . _:b555739861 "2"^^ . _:b555739841 . _:b32373192 . _:b555739860 "2"^^ . _:b555739863 "2"^^ . _:b32373261 . _:b555739862 "2"^^ . _:b32373270 . _:b555739857 "2"^^ . _:b555739840 . _:b555739856 "2"^^ . _:b32373291 . _:b555739859 "2"^^ . . . _:b555739858 "2"^^ . _:b555739780 . . _:b555739869 "2"^^ . _:b32373252 . _:b555739868 "2"^^ . _:b555739716 . _:b555739871 "2"^^ . . _:b555739870 "2"^^ . _:b555739865 "2"^^ . _:b555739864 "2"^^ . _:b555739875 . _:b555739867 "2"^^ . _:b555739866 "2"^^ . . _:b555739877 "2"^^ . _:b555739876 "2"^^ . . _:b32373196 . _:b555739876 . _:b555739740 . _:b555739760 . _:b555739873 "2"^^ . _:b555739872 "2"^^ . _:b32373242 "multiple trophic actions including axon guidance [70], synaptic plasticity [71], prevention of apoptosis [72,73], adult neurogenesis including in the course of CNS regeneration [74-76], which is believed to be impaired in neuroAIDS [>>77<<], and synaptic trophism [54]." . _:b555739875 "2"^^ . _:b555739874 "2"^^ . . . _:b555739774 . . . _:b32373257 "Nucleophosmin/B23, encoded by the Npm1 gene, is a nuclear chaperone implicated in the nuclear transport of Tat [>>96<<]." . . _:b32373216 . . _:b32373194 "Processing of Affymetrix microarrays was carried out as previously described, according to manufacturer\u2019s procedures [125,>>126<<]. All analyses were performed with R statistical software. We analyzed 11 samples (5 HIV-1 Tg rats; 6 controls) hybridized on Affymetrix Rat 230.2." . _:b555739741 . _:b32373219 . . _:b555739719 . . _:b32373234 "ErbB2/B4 receptors and their ligand neuregulin-1 (NRG1) are encoded by candidate susceptibility genes for schizophrenia [>>69<<]. Functional NRG1 receptors consist of ErbB4 homodimers or heterodimers between ErbB2, ErbB3 and ErbB4 since NRG1 binds ErbB3 and ErbB4, and ErbB2 and ErbB4 have intrinsic tyrosine kinase activity [69]." . _:b555739787 . . . _:b32373275 "These effects are at least in part mediated by recruitment of PI3K [>>111<<,114]. Additionally, chronic treatment with IGF-1 was protective in vitro against gp120-mediated neuronal damage and was synergistic with erythropoietin (EPO), at least in part, through cooperative activation of PI3K [115]." . _:b32373204 . _:b555739753 . _:b32373241 . _:b555739735 . . . . _:b32373286 . . _:b555739812 . . _:b555739823 . _:b32373268 . _:b32373292 . _:b32373222 "Dysregulations of genes related to Parkinson\u2019s disease and Huntington\u2019s disease and mitochondrial function, is consistent with previous studies suggesting mitochondrial dysfunction and oxidative stress as potential contributors to HAND [>>51<<]." . _:b555739747 . . _:b555739802 . . _:b32373195 "RT-PCR was carried out as previously described [>>125<<,127,128] with SYBR Green (BioRad) detection using an iQ5 Real-Time PCR Detection System (BioRad, Hercules, CA)." . _:b32373266 "The present results of increased PGD2 synthase (Ptgds), is in keeping with previous studies that showed elevated PGD2 levels in HIV-1-positive patients [>>42<<]. A potential role of prostaglandins in HIV-1 neuropathogenesis is also indicated by increased expression of the prostaglandin synthetic enzyme COX-2, which is also a characteristic of other degenerative conditions such as Alzheimer's" . . _:b32373250 . . . . _:b555739731 . . . _:b555739811 . . . . _:b555739874 . _:b555739785 . . _:b32373274 "IGF-1 therapy has shown potential in models of both Parkinson\u2019s disease [110,111] and Alzheimer's disease [112,>>113<<]. These effects are at least in part mediated by recruitment of PI3K [111,114]." . _:b555739845 . _:b32373246 . _:b32373273 "IGF-1 therapy has shown potential in models of both Parkinson\u2019s disease [110,111] and Alzheimer's disease [>>112<<,113]. These effects are at least in part mediated by recruitment of PI3K [111,114]." . _:b32373286 . . _:b32373288 . _:b555739771 . _:b32373258 . _:b555739791 . _:b555739804 . _:b32373237 . _:b32373186 _:b32373188 . _:b32373186 _:b32373189 . _:b32373186 _:b32373190 . . _:b32373256 . . . _:b32373291 "In fact, after the introduction of cART, HAND do not correlate with indicators of florid HIV replication such as plasma viral load and low CD4+ counts [4], but are correlated with synaptodendritic injury [17,>>18<<], which in experimental settings can be induced by HIV-1 products even in the absence of virus replication [19-21]." . . _:b32373186 _:b32373187 . _:b32373191 _:b32373192 . _:b32373205 "pathway analysis that we employed suggests key dysregulation in IFN regulated pathways, including ISG-15, which exerts antiviral activities through members of the Endosomal sorting complex required for transport (ESCRT) proteins [>>38<<]. ISG-15 was proposed to be a predictive biomarker for HAND [39,40]. In particular, ISG-15 was shown to correlate with neuropathology and viral load and ISG-15 CSF levels may be predictive of future neurocognitive impairments [38]." . _:b32373191 _:b32373193 . _:b32373191 _:b32373194 . _:b32373191 _:b32373195 . _:b32373191 _:b32373196 . _:b32373191 _:b32373197 . _:b32373191 _:b32373198 . _:b32373191 _:b32373199 . _:b32373295 "a gag/pol-deleted HIV-1 provirus under the LTR promoter [22], resulting in the co-expression of multiple HIV-1 proteins in disease-relevant central nervous system (CNS) cells such as microglia and astrocytes, but not in neurons [22,>>23<<]. Thus, the HIV-1 Tg rats differ from most other non-replicating small animal models expressing a single HIV-1 protein and from replicating models [24]." . _:b32373296 "Thus, the HIV-1 Tg rats differ from most other non-replicating small animal models expressing a single HIV-1 protein and from replicating models [>>24<<]. The construct used in HIV-1 Tg rats was previously used in mice where it was characterized by ectopic expression [25], possibly because of deficient interaction of Tat with the murine cyclin T [26]. Despite lack of virus replication and" . _:b32373297 . . _:b32373200 _:b32373220 . _:b32373200 _:b32373221 . _:b32373200 _:b32373222 . _:b32373200 _:b32373223 . _:b32373200 _:b32373216 . _:b555739736 . _:b32373217 . _:b32373200 _:b32373217 . _:b32373200 _:b32373218 . _:b32373200 _:b32373219 . _:b32373200 _:b32373228 . _:b32373200 _:b32373229 . _:b32373200 _:b32373230 . _:b555739839 . _:b32373200 _:b32373231 . _:b32373223 . _:b32373200 _:b32373224 . _:b32373200 _:b32373225 . _:b32373200 _:b32373226 . . _:b32373200 _:b32373227 . _:b32373200 _:b32373236 . _:b32373200 _:b32373237 . _:b555739757 . _:b32373200 _:b32373238 . _:b32373200 _:b32373239 . _:b32373200 _:b32373232 . _:b32373200 _:b32373233 . _:b32373200 _:b32373234 . _:b32373200 _:b32373235 . _:b32373200 _:b32373244 . _:b32373200 _:b32373245 . _:b32373200 _:b32373246 . _:b32373200 _:b32373247 . _:b32373200 _:b32373240 . . _:b32373200 _:b32373241 . _:b32373200 _:b32373242 . _:b32373200 _:b32373243 . . _:b32373211 "genes induced in the hippocampus of HIV-1 Tg rats were previously associated with neuroAIDS in humans including IGF binding proteins [41], prostaglandin D2 (PGD2) synthase [42], and the pro-alpha2 chain of type I collagen, Col1A2 [>>43<<]. Prostaglandins have been implicated in inflammation-induced working memory deficits [44] and imaging evidence supports that brain arachidonic acid metabolism in HIV-1 transgenic rats is upregulated [45]." . . _:b32373188 . _:b32373199 "alternation behavior (SAB) and the response bias were calculated with the formula below where n\u2009=\u2009number of choices, na\u2019\u2009=\u2009number of non-alternation responses, \u03C1R2\u2009=\u2009probability of a right turn, \u03C1L2\u2009=\u2009probability of a left turn [>>130<<]. The response bias corresponds to the tendency of an animal to favor one side over the other." . _:b32373189 . _:b32373200 _:b32373204 . _:b32373200 _:b32373205 . _:b32373190 . _:b32373200 _:b32373206 . _:b32373200 _:b32373207 . _:b32373200 _:b32373201 . . _:b32373200 _:b32373202 . _:b32373191 . _:b32373200 _:b32373203 . _:b32373200 _:b32373212 . _:b555739860 . _:b32373200 _:b32373213 . _:b555739723 . _:b32373279 . _:b32373200 _:b32373214 . _:b32373200 _:b32373215 . _:b32373200 _:b32373208 . _:b32373200 _:b32373209 . _:b32373200 _:b32373210 . _:b32373200 _:b32373211 . _:b555739738 . _:b32373186 . _:b32373224 . _:b32373187 . _:b32373236 . _:b32373225 . _:b32373196 . _:b32373197 . _:b32373198 . _:b32373247 . _:b32373220 . _:b32373199 . _:b555739819 . _:b32373192 . _:b32373193 . _:b32373194 . _:b32373195 . . . _:b32373204 . . . _:b32373205 . _:b32373206 . _:b32373236 "Mice that lack the ErbBs with intrinsic tyrosine kinase activity (ErbB2 and ErbB4) in the CNS have reduced dendritic spine density and behavioral abnormalities [>>53<<], possibly implicating this ErbB signaling in synaptodendritic injury." . _:b32373290 "In fact, after the introduction of cART, HAND do not correlate with indicators of florid HIV replication such as plasma viral load and low CD4+ counts [4], but are correlated with synaptodendritic injury [>>17<<,18], which in experimental settings can be induced by HIV-1 products even in the absence of virus replication [19-21]." . _:b32373207 . _:b32373221 . _:b32373200 . _:b32373201 . "PMC0" . _:b32373202 . _:b32373203 . _:b32373212 . _:b32373213 . _:b555739870 . . _:b32373214 . . . . . _:b32373215 . . _:b32373208 . _:b32373209 "Several other inflammation-related genes induced in the hippocampus of HIV-1 Tg rats were previously associated with neuroAIDS in humans including IGF binding proteins [>>41<<], prostaglandin D2 (PGD2) synthase [42], and the pro-alpha2 chain of type I collagen, Col1A2 [43]." . . _:b32373209 . _:b32373287 . _:b32373210 . . _:b32373282 . . _:b555739865 . _:b32373211 . . _:b32373220 . _:b555739852 . . _:b32373297 "The construct used in HIV-1 Tg rats was previously used in mice where it was characterized by ectopic expression [>>25<<], possibly because of deficient interaction of Tat with the murine cyclin T [26]." . _:b32373221 . . _:b32373222 . . _:b32373223 . _:b32373216 . _:b32373201 . _:b32373217 . _:b555739733 . . _:b32373294 "harbor a gag/pol-deleted HIV-1 provirus under the LTR promoter [22], resulting in the co-expression of multiple HIV-1 proteins in disease-relevant central nervous system (CNS) cells such as microglia and astrocytes, but not in neurons [>>22<<,23]. Thus, the HIV-1 Tg rats differ from most other non-replicating small animal models expressing a single HIV-1 protein and from replicating models [24]." . _:b32373218 . _:b32373244 . _:b32373219 . _:b32373228 . _:b555739729 . _:b32373197 "The relative amounts of target mRNA were determined by the \u0394Ct method using \u03B2-actin for normalization [>>129<<]. Statistical significance of differences between HIV-1 Tg rats and controls was determined by unpaired Student\u2019s t-test." . _:b32373229 . _:b32373238 . . _:b32373230 . . _:b32373286 . _:b555739772 . _:b32373231 . . _:b32373224 . _:b555739867 . _:b32373282 "However, as PI3K appears to play a role in the regulation of the HIV-1 LTR promoter and virus latency [>>122<<,123], activation of PI3K in the cells that harbor the provirus may increase levels of expression of HIV-1 products, potentially leading to detrimental effects on cognition." . _:b32373225 . . _:b32373226 . _:b32373245 "signaling pathways relevant to trophic support such as the PI3K-mTOR signaling pathway, which mediates a vast array of trophic signals [78]; the LKB1 pathway, which is key to neuronal survival following mitochondrial insults [>>79<<] and cross-talks with the PI3K-mTOR pathway; and the ILK pathway, which is involved in mediating trophic signals of the extracellular matrix and trophic factors as well as in the anti-apoptotic effect of the PI3K pathway [80]." . . _:b32373227 . . _:b32373258 . _:b32373236 . _:b32373190 "Rats were tested in the dark in spontaneous alternations in the T-Maze, which is a paradigm sensitive to prefrontal cortex and hippocampal impairments [>>29<<-32]. Visual cues were not provided in the T-Maze paradigm, as done by others [33], to minimize the influence of cataracts in HIV-1 Tg rats. HIV-1 Tg rats exhibited a marked decrease of alternation behavior (SAB) compared to control rats" . _:b32373237 . . _:b32373238 . _:b555739803 . _:b32373239 . . _:b555739764 . _:b32373285 "HIV-associated dementia, opportunistic infections and neoplasms are significantly reduced since the introduction of combination antiretroviral therapy (cART) [>>1<<-4]. However, decreased HIV-associated dementia has been associated with an increased prevalence of milder and chronic forms of HIV-associated neurocognitive disorders (HAND) and HIV-associated major depressive disorder along with" . _:b32373232 . _:b555739745 . _:b32373201 "In this regard it should be noted that spontaneous alternation behavior (SAB) has been used in aged rats with visual impairments [>>34<<] and to compare anophthalmic mutant mice to wild-type controls [35]." . . _:b32373233 . _:b32373234 . _:b32373240 . _:b32373235 . _:b32373244 . _:b32373279 . _:b32373245 . _:b555739824 . _:b555739728 . _:b32373246 . . _:b32373247 . _:b32373213 . . _:b32373240 . _:b32373259 "This is especially needed in neuroAIDS as no targeted therapy other than cART is currently recommended for the management of HAND [>>100<<,101]. Adjunctive therapies for HAND explored to date include the low-affinity antagonist of the NMDA type glutamate receptor memantine, the calcium channel blocker nimodipine, and the monoamine oxidase B inhibitor selegiline, in addition" . _:b32373241 . _:b32373264 "Selegiline is a drug used for the treatment of early-stage Parkinson\u2019s disease, depression and dementia [104,>>105<<]." . . _:b32373242 . _:b32373243 . _:b555739868 . . _:b32373275 . . . _:b32373272 . . _:b32373210 . _:b555739832 . _:b32373214 . _:b555739829 . _:b32373215 . _:b32373251 . _:b555739720 . . _:b32373292 . _:b32373286 . _:b32373197 . _:b32373191 "methods" . _:b555739805 . . _:b32373292 "florid HIV replication such as plasma viral load and low CD4+ counts [4], but are correlated with synaptodendritic injury [17,18], which in experimental settings can be induced by HIV-1 products even in the absence of virus replication [>>19<<-21]. Therefore, there is a need to investigate the pathologic consequences of the expression of low levels of multiple HIV-1 proteins in disease relevant cell types." . . . . _:b32373235 . _:b32373234 . . _:b32373233 . _:b32373230 "The IGF activated gene TDAG51/PHLDA1 [>>63<<], which is expressed in both neurons and glial cells [64], is implicated in insulin signaling [65] and has been shown to have differential effects on susceptibility to apoptosis [66-68]." . _:b32373235 "Functional NRG1 receptors consist of ErbB4 homodimers or heterodimers between ErbB2, ErbB3 and ErbB4 since NRG1 binds ErbB3 and ErbB4, and ErbB2 and ErbB4 have intrinsic tyrosine kinase activity [>>69<<]. Mice that lack the ErbBs with intrinsic tyrosine kinase activity (ErbB2 and ErbB4) in the CNS have reduced dendritic spine density and behavioral abnormalities [53], possibly implicating this ErbB signaling in synaptodendritic injury." . . _:b32373298 "The construct used in HIV-1 Tg rats was previously used in mice where it was characterized by ectopic expression [25], possibly because of deficient interaction of Tat with the murine cyclin T [>>26<<]. Despite lack of virus replication and production, HIV-1 Tg rats have a progressive clinical presentation leading to a picture reminiscent of some of AIDS features later in life that includes immunological abnormalities and neurological" . . _:b32373202 . . . . . . _:b32373254 "In apparent agreement with the dysregulation of these pathways, evidence suggestive of altered phospholipid metabolism has been reported in HIV-1 patients [>>92<<,93] and peroxisome dysregulation can be indicative of altered brain oxidative balance associated with HIV-1 [94]." . _:b555739712 . . . _:b555739857 . _:b32373223 "in neuronal trophism and synaptic maturation and plasticity that were found to be differentially regulated in HIV-1 Tg rats involve IGF, ErbB and netrin, all of which have been shown to exert trophic actions on dendritic spines [>>52<<-55], suggesting that dysregulation of these pathways can contribute to the synaptodendritic injury seen in neuroAIDS [17,18]." . _:b555739786 . _:b555739851 . . _:b555739814 . _:b32373263 "Selegiline is a drug used for the treatment of early-stage Parkinson\u2019s disease, depression and dementia [>>104<<,105]." . . _:b32373300 "replication and production, HIV-1 Tg rats have a progressive clinical presentation leading to a picture reminiscent of some of AIDS features later in life that includes immunological abnormalities and neurological manifestations [22,>>27<<]." . . _:b32373217 . _:b32373278 . . _:b32373207 . . _:b32373245 . _:b555739759 . _:b32373276 . _:b555739816 . . _:b32373224 "Tg rats involve IGF, ErbB and netrin, all of which have been shown to exert trophic actions on dendritic spines [52-55], suggesting that dysregulation of these pathways can contribute to the synaptodendritic injury seen in neuroAIDS [>>17<<,18]." . _:b32373267 .