Biomedical subjects

Italo Mocchetti

Publications and source records attributed to Italo Mocchetti.

16 recordsLinked to original sources

PubMed2006

Axonal transport of human immunodeficiency virus type 1 envelope protein glycoprotein 120 is found in association with neuronal apoptosis.

Patients infected by human immunodeficiency virus type 1 (HIV-1) develop acquired immune deficiency syndrome-associated dementia complex (ADC), a disorder characterized by a broad spectrum of motor impairments and cognitive deficits. The number of cells in the brain that are productively infected by HIV-1 is relatively small and consists predominantly of macrophages and microglia, yet HIV-1 causes widespread neuronal loss. A better understanding of the pathogenic mechanisms mediating HIV-1 neurotoxicity is crucial for developing effective neuroprotective therapies against ADC. The HIV-1 envelope glycoprotein 120 (gp120), which is shed from the virus, is one of the agents causing neuronal cell death. However, the cellular mechanisms underlying its neurotoxic effect remain unclear. We report that gp120 injected into the rat striatum or hippocampus is sequestered by neurons and subsequently retrogradely transported to distal neurons that project to these brain areas. Cleaved caspase-3 and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling, hallmarks of apoptosis, were seen in neurons internalizing and transporting gp120. The retrograde transport of gp120 and apoptosis were mediated by the chemokine receptor CXCR4 because AMD3100, a selective CXCR4 inhibitor, blocked both events. Furthermore, colchicine or nocodazole, two inhibitors of intracellular trafficking, abolished gp120-mediated apoptosis in distal areas. These results indicate that axonal transport of gp120 might play a role in HIV-1-mediated widespread neuronal cell death.

Animals↗

PubMed2006

CAAT/enhancer-binding protein delta and cAMP-response element-binding protein mediate inducible expression of the nerve growth factor gene in the central nervous system.

Nerve growth factor (NGF) synthesis in the rat cerebral cortex is induced by the beta2-adrenergic receptor agonist clenbuterol (CLE). Because NGF is a crucial neurotrophic factor for basal forebrain cholinergic neurons, defining the mechanisms that regulate its transcription is important for developing therapeutic strategies to treat pathologies of these neurons. We previously showed that the transcription factor CCAAT/enhancer-binding protein delta (C/EBPdelta) contributes to NGF gene regulation. Here we have further defined the function of C/EBPdelta and identified a role for cAMP response element-binding protein (CREB) in NGF transcription. Inhibition of protein kinase A in C6-2B glioma cells suppressed CLE induction of an NGF promoter-reporter construct, whereas overexpression of protein kinase A increased NGF promoter activity, particularly in combination with C/EBPdelta. A CRE-like site that binds CREB was identified in the proximal NGF promoter, and C/EBPdelta and CREB were found to associate with the NGF promoter in vivo. Deletion of the CRE and/or C/EBP sites reduced CLE responsiveness of the promoter. In addition, ectopic expression of C/EBPdelta in combination with CLE treatment increased endogenous NGF mRNA levels in C6-2B cells. C/EBPdelta null mice showed complete loss of NGF induction in the cerebral cortex following CLE treatment, demonstrating a critical role for C/EBPdelta in regulating beta2-adrenergic receptor-mediated NGF expression in vivo. Thus, our findings demonstrate a critical role for C/EBPdelta in regional expression of NGF in the brain and implicate CREB in CLE-induced NGF gene transcription.

Adrenergic beta-Agonists↗

PubMed2006

Semisynthetic sphingoglycolipid LIGA20 is neuroprotective against human immunodeficiency virus-gp120-mediated apoptosis.

Apoptosis and neuronal atrophy are commonly seen in patients infected with the human immunodeficiency virus type 1 (HIV-1) in the late phase of infection. The HIV-1 envelope glycoprotein gp120 has been suggested to be a causal agent of neuronal loss. Therefore, blocking gp120 neurotoxicity may be an effective way to reduce the neuronal degeneration seen in HIV patients. Brain-derived neurotrophic factor (BDNF) prevents gp120-mediated apoptosis in cerebellar granule cells. However, BDNF poorly crosses the blood-brain barrier and therefore may not be a suitable therapy for HIV patients. LIGA20 is a semisynthetic sphingoglycolipid that may be a valid alternative to BDNF. In fact, it has been shown that LIGA20 mimics the neuroprotective properties of BDNF. The present study was undertaken to characterize the relative potency of LIGA20 to antagonize gp120-mediated apoptosis. Cerebellar granule cells were exposed to gp120IIIB (5 nM) or stromal-cell derived factor-1 (SDF), the natural ligand for the CXCR4 receptor to which gp120 binds, alone or in combination with LIGA20 (5 microM), and cell death/survival was determined 12 and 24 hr later by various markers of apoptosis. LIGA20 blocked the neurotoxic effect of gp120 and SDF. The neurotrophic effect of LIGA20 was reversed by K252a, a tyrosine kinase inhibitor used to block TrkB signaling, suggesting the involvement of TrkB activation. These findings provide the rationale for exploring the ability of compounds that mimic BDNF activity to reduce neuronal cell death in HIV-1-positive patients.

Animals↗

PubMed2006

Intrastriatal administration of human immunodeficiency virus-1 glycoprotein 120 reduces glial cell-line derived neurotrophic factor levels and causes apoptosis in the substantia nigra.

Uninfected neurons of the substantia nigra (SN) degenerate in human immunodeficiency virus (HIV)-positive patients through an unknown etiology. The HIV envelope glycoprotein 120 (gp120) causes apoptotic neuronal cell death in the rodent striatum, but its primary neurotoxic mechanism is still under investigation. Previous studies have shown that gp120 causes neurotoxicity in the rat striatum by reducing brain-derived neurotrophic factor (BDNF). Because glial cell line-derived neurotrophic factor (GDNF) and BDNF are neurotrophic factors crucial for the survival of dopaminergic neurons of the SN, we investigated whether gp120 reduces GDNF and BDNF levels concomitantly to induce apoptosis. Rats received a microinjection of gp120 or vehicle into the striatum and were sacrificed at various time intervals. GDNF but not BDNF immunoreactivity was decreased in the SN by 4 days in gp120-treated rats. In these animals, a significant increase in the number of caspase-3- positive neurons, both tyrosine hydroxylase (TH)-positive and -negative, was observed. Analysis of TH immunoreactivity revealed fewer TH-positive neurons and fibers in a medial and lateral portion of cell group A9 of the SN, an area that projects to the striatum, suggesting that gp120 induces retrograde degeneration of nigrostriatal neurons. We propose that dysfunction of the nigrostriatal dopaminergic system associated with HIV may be caused by a reduction of neurotrophic factor expression by gp120.

AIDS Dementia Complex↗

PubMed2005

The nitrosteroid NCX 1015, a prednisolone derivative, improves recovery of function in rats after spinal cord injury.

Glucocorticoids, given at high-doses, improve recovery of function after spinal cord injury (SCI) in animals. However, side effects combined with a limited efficacy in clinical trials have restricted their usefulness for treatment of SCI patients. Recent studies have shown that incorporation of the nitric oxide releasing moiety into the glucocorticoid structure enhances anti-inflammatory properties and reduces side effects. One compound, a derivative of prednisolone (PRE), (NCX 1015, prednisolone 21 [(4'nitrooxymethyl)benzoate]), has interesting pharmacological properties. Therefore, we investigated its effects on apoptosis and recovery of function in rats after SCI. Rats received subcutaneously vehicle, NCX 1015 or PRE (37 micromol/kg, each) 3.5 h after a standardized thoracic lesion. The treatment was continued once a day for 3 days and the effect of both steroids on apoptosis was examined by immunohistochemistry 24 h after the last injection. NCX 1015 but not PRE reduced TUNEL and activated caspase 3 in both white and ventral gray matter as well as tumor necrosis factor immunoreactivity in ventral horn motorneurons, suggesting that NCX 1015 reduces SCI-induced apoptosis. The effect of NCX 1015 on motor function was then examined by a standard locomotion rating scale (BBB) starting at 1 day after injury and continuing up to 14 days. NCX 1015 improved significantly locomotor activity by 4 days after injury, whereas PRE had an effect equivalent to that of vehicle, thus providing a correlation between the antiapoptotic effect of NCX1015 and its ability to improve recovery of function. The data suggest that NCX 1015 might be a novel experimental therapeutic compound for recovery of function in SCI patients.

Animals↗

PubMed2005

Brain-derived neurotrophic factor is neuroprotective against human immunodeficiency virus-1 envelope proteins.

Human immunodeficiency virus type 1 (HIV-1)-positive patients in the late phase of infection develop AIDS dementia complex, an array of neurological complications that include extrapyramidal symptoms, cognitive impairments, and psychiatric disturbances. Brains of these patients exhibit brain injury. The HIV-1 envelope glycoprotein 120 (gp120) has been suggested to be a causal agent of neuronal loss; however, several strains of gp120 exist during the infection and the relative neurotoxic potential of each strain is presently unknown. Using cultured cerebellar granule neurons, we determined whether two strains of gp120, gp120IIIB and gp120BaL, which bind to CXCR4 and CCR5 chemokine receptors, respectively, induce cell death. Apoptotic cell death and activated caspase-3 were evident within a few hours in neurons exposed to low nanomolar concentrations of either gp120IIIB or gp120BaL. However, the neurotoxic effect of gp120IIIB was more rapid and occurred at lower concentrations than that of gp120BaL, suggesting that cerebellar granule cells may be more sensitive to apoptotic signals activated by the CXCR4 receptor. The neurotrophin brain-derived neurotrophic factor (BDNF) has been shown to block neuronal apoptosis. Therefore, we examined whether BDNF protects against both strains of gp120. Preexposure of cerebellar granule cells to BDNF prior to both gp120s decreased apoptosis and consequently enhanced their survival. These findings underlie the rationale for exploring the ability of BDNF to reduce HIV-1-mediated neuronal cell death in vivo.

Animals↗

PubMed2004

Synergistic effect of dexamethasone and beta-adrenergic receptor agonists on the nerve growth factor gene transcription.

Activation of beta-adrenergic receptor (betaAR) increases the synthesis of nerve growth factor (NGF) in the brain and in C6-2B glioma cells. However, in the brain, the betaAR-mediated increase in NGF expression appears to require the presence of glucocorticoids, suggesting that NGF promoter may be sensitive to cAMP and glucocorticoid-dependent transcription factors. We tested this hypothesis by exposing C6-2B glioma cells to dexamethasone (DEX) in combination with agents that increase cAMP levels and examining the DNA binding activity of two cAMP-dependent transcription factors that regulate NGF expression: cAMP responsive element binding protein (CREB) and CCAAT/enhancer binding protein delta (C/EBPdelta). Electrophoretic mobility shift assays revealed that the beta(2)AR agonist clenbuterol (CLE) or high levels of cAMP elicited a time-dependent increase in C/EBPdelta binding activity as well as phosphorylated CREB (P-CREB). When DEX, which per se showed little effect on these transcription factors, was combined with CLE, dibutyryl cAMP or isoproterenol, enhanced induction of P-CREB and C/EBP binding activity as well as NGF mRNA was observed. Moreover, the increase in NGF mRNA in the presence of DEX was prolonged compared to that obtained by CLE or other cAMP inducing agents alone. In fact, NGF mRNA levels remained significantly elevated at least for 24 h. These studies suggest that the synergistic effect of DEX on the induction of NGF mRNA may include the ability of this glucocorticoid to potentiate the betaAR-mediated induction of transcription factors.

Adrenergic beta-Agonists↗

PubMed2004

The chemokine receptor CXCR4 and not the N-methyl-D-aspartate receptor mediates gp120 neurotoxicity in cerebellar granule cells.

The human immunodeficiency virus type 1 (HIV-1) glycoprotein gp120 causes neuronal cell death; however, the molecular mechanisms of the neurotoxic effect remain largely unresolved. It has been suggested that gp120 evokes cell death by inducing the release of neurotoxins, including glutamate. The objective of this work was to examine the role of glutamate in gp120-mediated neurotoxicity. We used as an experimental tool cerebellar granule cells prepared from 8-day-old rat cerebella, in which both glutamate and gp120 cause cell death. Cerebellar granule neurons were exposed to gp120 or glutamate alone or in combination with the glutamate receptor antagonist MK801 as well as other antiglutamatergic compounds. Cell viability was measured at various times by using several markers of cell death and apoptosis. MK801, at a concentration that blocked glutamate-induced neuronal cell death, failed to prevent gp120-mediated apoptotic cell death. Moreover, interleukin-10, which has previously been shown to block glutamate toxicity in these neurons, was not neuroprotective against gp120. Because gp120 toxicity is mediated by activation of the chemokine receptor CXCR4, neurons were incubated with the CXCR4 inhibitor AMD3100. This compound prevented gp120- but not glutamate-mediated cell death. These findings suggest that gp120 is toxic to neurons even in the absence of the virus and that the toxic mechanism involves primarily activation of CXCR4 receptor. Therefore, antagonists to the CXCR4 receptor may be more suitable compounds for inhibiting HIV-1 neurotoxicity.

Animals↗

PubMed2004

Human immunodeficiency virus type 1 protein gp120 causes neuronal cell death in the rat brain by activating caspases.

Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system is associated with microglia activation and neuronal apoptosis, alterations that are also caused by the HIV-1 envelope glycoprotein 120 (gp120) alone. This study was undertaken to examine the onset of gp120 neurotoxicity, the type of cell death and which cells of the adult rat brain are more sensitive to the toxic action of gp120. Gp120 or vehicle were injected chronically (daily for 3 or 7 days) into the lateral ventricle. Magnetic resonance imaging revealed hypertensive areas in the cortical and hippocampal gray matter in gp120-treated rats 7-10 days after the first injection, suggesting vasogenic edema. This phenomenon was accompanied by an enlargement of the lateral and third ventricles. Immunohistochemical analyses were then carried out to examine the toxic effect of gp120 at a cellular level. Several markers of apoptosis, including activated caspase-3 were observed at both 3 and 7 days throughout brains of gp120-treated rats, especially in the cerebral cortex. In this area, most of the apoptotic cells exhibited a pyramidal shape and were Nissl positive, indicative of neurons. Few non-neuronal cells exhibited signs of apoptosis. The results of the present study support the notion that gp120 is neurotoxic in vivo and provide evidence that gp120 activates a caspase-dependent apoptotic pathway.

Animals↗

PubMed2004

Human immunodeficiency virus type 1 glycoprotein gp120 reduces the levels of brain-derived neurotrophic factor in vivo: potential implication for neuronal cell death.

Neuronal loss has been observed in post mortem brains of patients with human immunodeficiency virus type 1 (HIV-1). Experimental evidence has implicated HIV-1-derived envelope glycoprotein 120 (gp120) in the neuronal cell death observed in these patients. However, the intrinsic mechanisms by which gp120 causes neurotoxicity are still unknown. We have recently shown that the neurotoxic effect of gp120 in vitro is reduced by brain-derived neurotrophic factor (BDNF). We therefore tested the hypothesis that low levels of BDNF render neurons more sensitive to gp120. Gp120 was injected acutely into the striatum of BDNF heterozygous mice and wild-type littermates. BDNF heterozygous mice exhibited more apoptotic neurons in the striatum than wild-type mice, suggesting that BDNF is neuroprotective also in vivo. Because several neurodegenerative disorders are characterized by lack of trophic support, we tested the hypothesis that gp120 may cause apoptosis by reducing BDNF expression. Gp120 was injected acutely in the rat striatum and BDNF levels determined by a two-site immunoassay at various times after the injection. Gp120 elicited a dramatic decrease in BDNF protein levels by 24 h. Reduced BDNF levels were still present at 4 days. Cellular localization of BDNF immunoreactivity revealed that gp120 decreases BDNF immunoreactivity mainly in neuronal processes. This effect of gp120 precedes the peak of caspase-3 activation and neuronal cell death. We propose that one of the mechanisms whereby gp120 causes neurotoxicity is a reduction of the neurotrophic factor environment crucial for cell survival.

Animals↗

PubMed2004

Autocrine regulation of nerve growth factor expression by Trk receptors.

Activation of the neurotrophin receptor Trk induces the release of neurotrophins. However, little is known about the ability of released neurotrophins to modulate their own synthesis in an autocrine manner. As a step towards understanding the role of Trk in regulating the synthesis of neurotrophins, we exposed NIH-3T3 cells expressing TrkA or TrkC receptors to their cognate ligands as well as to GM1, a ganglioside that activates TrkA and TrkC by inducing the release of neurotrophin-3. Nerve growth factor and neurotrophin-3 synthesis were then determined by measuring the relative levels of protein and mRNA. TrkA-expressing cells exposed to human recombinant nerve growth factor exhibited higher levels of nerve growth factor mRNA. Human recombinant neurotrophin-3 evoked an increase in nerve growth factor mRNA in both TrkA and TrkC-expressing cells. GM1 elicited a time-dependent increase in nerve growth factor protein and mRNA in NIH-3T3 cells expressing TrkA or TrkC receptor but not in wild-type cells. Surprisingly, GM1 failed to change neurotrophin-3 levels. The ability of GM1 to increase nerve growth factor mRNA levels was blocked by TrkC-IgG but not by TrkB-IgG receptor body. These data suggest that released neurotrophin-3 may activate a positive autocrine loop of nerve growth factor synthesis by Trk activation.

Analysis of Variance↗

PubMed2004

Brain-derived neurotrophic factor activation of TrkB protects neurons from HIV-1/gp120-induced cell death.

Patients with the human immunodeficiency virus type 1 (HIV-1) develop in the late phase of infection a complex of neurological signs termed Acquired Immune Deficiency Syndrome-Related Dementia (ADC). These patients exhibit cortical and subcortical atrophy. Considerable experimental data indicate that the HIV-1 envelope glycoprotein gp120 may be one of the agents causing neuronal cell death. Gp120 causes neuronal cell death both in vitro and in vivo by activating a caspase-dependent apoptotic pathway, and in particular caspase-3. The neurotrophin brain-derived neurotrophic factor (BDNF) has been shown to prevent gp120-mediated apoptosis of cerebellar granule cells by inhibiting caspase-3 activation. However, the signal transduction pathway that contributes to the neuroprotective effects of BDNF has not been determined. BDNF binds with high affinity to the tyrosine kinase receptor TrkB and activates different intracellular signaling cascade including the extracellular signal-related kinases (ERK) and the phosphatidylinositol 3-kinase (PI3-K). Pharmacological inhibition of TrkB or ERK1/2, but not PI3-K, greatly reduced the ability of BDNF to block gp120-mediated apoptosis of cerebellar granule cells. These findings suggest that TrkB-mediated activation of ERK1/2 is the main signaling pathway that contributes to neuroprotection against gp120.

Animals↗

PubMed2003

Brain-derived neurotrophic factor inhibits human immunodeficiency virus-1/gp120-mediated cerebellar granule cell death by preventing gp120 internalization.

The human immunodeficiency virus type 1 (HIV-1) envelope protein gp120 has been implicated in the pathogenesis of HIV-1 dementia. Thus, inhibition of gp120 activity could reduce HIV toxicity in the brain. We have used primary cultures of rat cerebellar granule cells to examine mechanisms whereby gp120 causes cell death and to characterize neuroprotective agents. gp120 induced a time- and concentration-dependent apoptotic cell death, which was caspase-3-mediated but caspase-1 independent, and was totally blocked by the irreversible caspase-3-like protease inhibitor N-acetyl-Asp-Glu-Val-Asp-chloromethylketone. Caspase-3 activation was observed only in neurons that internalize gp120, indicating that internalization is key to gp120 toxicity. Because brain-derived neurotrophic factor (BDNF) prevents caspase-3-mediated neuronal cell death, we examined whether BDNF could prevent gp120-mediated apoptosis. Preincubation of neurons with BDNF before the addition of gp120 reduced caspase-3 activation, and consequently rescued 80% of neurons from apoptosis. Most importantly, BDNF reduced the levels of CXC chemokine receptor-4 (CXCR4), a receptor that mediates HIV-1 gp120-induced apoptosis. This effect correlated with the ability of BDNF to reduce gp120 internalization and apoptosis. Moreover, BDNF blocked the neurotoxic effect of stromal-derived factor-1alpha, a natural ligand for CXCR4, further establishing a correlation between neuroprotection and downregulation of CXCR4. We propose that BDNF may be a valid therapy to slow down the progression of HIV/gp120-mediated neurotoxicity.

Animals↗

PubMed2002

Gangliosides activate Trk receptors by inducing the release of neurotrophins.

We used NIH-3T3 fibroblasts expressing the different Trk receptors to examine whether GM1 ganglioside and its semisynthetic derivative LIGA20 activate various neurotrophin receptors. GM1 induced autophosphorylation of TrkC more potently than TrkA or TrkB receptors. In contrast, LIGA20 activated TrkB tyrosine phosphorylation only. Therefore, Scatchard analysis was performed to determine whether GM1 binds to TrkC. GM1 failed to displace neurotrophin-3 binding, suggesting that this ganglioside does not act as a ligand for Trk receptors. In addition, GM1 failed to induce autophosphorylation of a chimeric receptor consisting of the extracellular domain of the tumor necrosis factor receptor and the intracellular domain of TrkA, suggesting that GM1 does not affect the tyrosine kinase domain. We next determined whether GM1 induces the release of neurotrophins from fibroblast cells. GM1 induced a rapid and significant increase in the amount of neurotrophin-3, but not other neurotrophins. This effect was independent of the presence of Trk because K252a did not prevent GM1-mediated release of neurotrophin-3. Moreover, GM1-mediated TrkC autophosphorylation was blocked by TrkC-IgG (but not TrkB-IgG) receptor bodies, further suggesting that GM1 activates TrkC by inducing the release of neurotrophin-3. This hypothesis was also tested in cultured cerebellar granule cells. GM1 induced neurotrophin-3 (but not brain-derived neurotrophic factor or nerve growth factor) release. In contrast, LIGA20 increased the secretion of brain-derived neurotrophic factor. Our data show that gangliosides may activate different Trk receptors by differentially affecting the release of neurotrophins.

3T3 Cells↗

PubMed2002

Gangliosides prevent excitotoxicity through activation of TrkB receptor.

Gangliosides protect cerebellar granule cells from excitotoxicity; however, their mechanism of action remains to be fully characterized. GM1 ganglioside has been shown to activate Trk, the tyrosine kinase receptor implicated in the neuroprotective properties of the neurotrophins. In these studies, we used primary cultures of cerebellar granule cells to determine whether gangliosides exert neuroprotective effect via the activation of Trk receptors. We first examined the relative potency of the neurotrophins, brain derived neurotrophic factor (BDNF), neurotrophin-3 and nerve growth factor to prevent glutamate-mediated apoptosis. BDNF was the only neurotrophin that elicited a complete neuronal protection against glutamate. GM1 and its semisynthetic compound LIGA20 also prevented glutamate toxicity, however, LIGA20 was more potent than GM1. Both LIGA20 and BDNF blocked glutamate-mediated activation of caspase-3 and consequently apoptosis; however, the anticaspase-3 activity was seen only when these compounds were added to the cultures several hours before glutamate, suggesting that LIGA20 and BDNF share an identical molecular mechanism. To test this hypothesis, we compared the ability of LIGA20 and BDNF to activate TrkB. Both compounds elicited a similar time-dependent increase in Trk tyrosine phosphorylation. Moreover, the neuroprotective effect of BDNF and LIGA20 was abolished in neurons exposed to the Trk tyrosine kinase inhibitor k252a, demonstrating a relationship between neuroprotection and activation of Trk receptors. Our data suggest that by activating the Trk neurotrophin receptors, gangliosides may be used as neuroprotective agents.

Journal Article↗

PubMed2002

Antidepressant treatments induce the expression of basic fibroblast growth factor in cortical and hippocampal neurons.

New experimental evidence suggests that the mechanism of action of antidepressants includes the induction of neurotrophic factor synthesis in selected brain areas. The present study is aimed at establishing whether prolonged antidepressant treatments increase the expression of basic fibroblast growth factor (FGF2), a polypeptide growth factor that has a broad neurotrophic activity in the adult central nervous system. Rats received a single dose or long-term (3 weeks) administration of desipramine (DMI), fluoxetine (FLU), and mianserin (MIA), then were sacrificed at 5 and 24 h after the last injection. RNase protection assay and Western blot analysis revealed that all antidepressant drugs elicited an anatomically specific increase in FGF2 mRNA and protein. The increase in FGF2 mRNA after a single injection was seen only at 5 h after the injection and was restricted to the entorhinal cortex, whereas the effect of the long-term treatments lasted up to 24 h and occurred in the entire cortex and hippocampus. Immunohistochemical analysis of FGF2 immunoreactivity was carried out to investigate which cell types responded to the antidepressant treatments. DMI and MIA increased FGF2 proteins predominantly in neurons of layer V throughout the cerebral cortex and in some neurofilament-positive cells of the hippocampus. FLU increased FGF2 immunoreactivity mainly in neurofilament-positive cells of the hippocampus. These findings may explain the therapeutic efficacy of antidepressants in affective disorders.

Animals↗