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HIV-1 Tat and cocaine mediated synaptopathy in cortical and midbrain neurons is prevented by the isoflavone Equol.

Bertrand SJ, Hu C, Aksenova MV, Mactutus CF, Booze RM - Front Microbiol (2015)

Bottom Line: In addition, the synapse-protective effects of either R-Equol (RE) or S-Equol (SE; derivatives of the soy isoflavone, daidzein) were determined.Individually, neither low concentrations of HIV-1 Tat (10 nM) nor low concentrations of cocaine (1.6 μM) had any significant effect on F-actin puncta number; however, the same low concentrations of HIV-1 Tat + cocaine in combination significantly reduced dendritic synapses.This synaptic reduction was prevented by pre-treatment with either RE or SE, in an estrogen receptor beta dependent manner.

View Article: PubMed Central - PubMed

Affiliation: Laboratory Program in Behavioral Neuroscience, Department of Psychology, University of South Carolina Columbia, SC, USA.

ABSTRACT
Illicit drugs, such as cocaine, are known to increase the likelihood and severity of HIV-1 associated neurocognitive disorders (HAND). In the current studies synaptic integrity was assessed following exposure to low concentrations of the HIV-1 viral protein Tat 1-86B, with or without cocaine, by quantifying filamentous actin (F-actin) rich structures (i.e., puncta and dendritic spines) on neuronal dendrites in vitro. In addition, the synapse-protective effects of either R-Equol (RE) or S-Equol (SE; derivatives of the soy isoflavone, daidzein) were determined. Individually, neither low concentrations of HIV-1 Tat (10 nM) nor low concentrations of cocaine (1.6 μM) had any significant effect on F-actin puncta number; however, the same low concentrations of HIV-1 Tat + cocaine in combination significantly reduced dendritic synapses. This synaptic reduction was prevented by pre-treatment with either RE or SE, in an estrogen receptor beta dependent manner. In sum, targeted therapeutic intervention with SE may prevent HIV-1 + drug abuse synaptopathy, and thereby potentially influence the development of HAND.

No MeSH data available.


Related in: MedlinePlus

R-Equol and SE prevented HIV-1 Tat + cocaine synaptic loss via a selective estrogen receptor (ERβ) dependent mechanism. Cortical neurons were pre-treated for 1 h with either MPP (ERα), PHTPP (ERβ), or G15 (GPR30) prior to treatment with either RE (A) or SE (B) to identify which specific ER subtype was necessary for equol-mediated synaptic protection from HIV-1 Tat + cocaine. We found that pre-treatment with PHTPP (ERβ) inhibited both the RE (panel A) and SE (panel B) induced synaptic protection in HIV-1 Tat + cocaine treated cortical neurons. (A) HIV-1 Tat + cocaine exposed neurons pre-treated with either MPP or G15, and subsequently RE, had normal levels of dendritic F-actin puncta (i.e., not significantly different from vehicle-treated controls, p > 0.05). In contrast, PHTPP-treated neurons had a significant loss of dendritic F-actin puncta compared to controls (p ≤ 0.05) and were not significantly different from HIV-1 Tat + cocaine treated dendrites (p > 0.05), indicating that PHTPP inhibited RE-induced synaptic protection. Mean ± SEM, ∗p ≤ 0.05. (B) HIV-1 Tat + cocaine exposed neurons pre-treated with either MPP or G15, and subsequently SE, had normal levels of dendritic F-actin puncta (i.e., not significantly different from vehicle-treated controls, p > 0.05). In contrast, PHTPP-treated neurons had a significant loss of dendritic F-actin puncta compared to controls (p ≤ 0.05) and were not significantly different from HIV-1 Tat + cocaine treated dendrites (p > 0.05), indicating that PHTPP inhibited SE-induced synaptic protection. Mean ± SEM, ∗p ≤ 0.05. (C–J) The ERβ antagonist PHTPP significantly blocked equol-mediated protection from HIV-1 Tat + cocaine in cortical neurons. PHTPP pre-treated, SE(I)/RE(J) treated, neurons lacked a fine dendritic network and had reduced dendritic branching, similar characteristics to those in non pre-treated HIV-1Tat + cocaine neurons (D). In contrast, vehicle (C), HIV-1 Tat (10 nM; G), cocaine (H), and SE(E)/RE(F) treated neurons had robust dendrites with complex branching patterns and a lack of aberrant morphology such as bundling or beading. Phalloidin/F-actin(green) and MAP-2 (blue); 20× magnification.
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Figure 3: R-Equol and SE prevented HIV-1 Tat + cocaine synaptic loss via a selective estrogen receptor (ERβ) dependent mechanism. Cortical neurons were pre-treated for 1 h with either MPP (ERα), PHTPP (ERβ), or G15 (GPR30) prior to treatment with either RE (A) or SE (B) to identify which specific ER subtype was necessary for equol-mediated synaptic protection from HIV-1 Tat + cocaine. We found that pre-treatment with PHTPP (ERβ) inhibited both the RE (panel A) and SE (panel B) induced synaptic protection in HIV-1 Tat + cocaine treated cortical neurons. (A) HIV-1 Tat + cocaine exposed neurons pre-treated with either MPP or G15, and subsequently RE, had normal levels of dendritic F-actin puncta (i.e., not significantly different from vehicle-treated controls, p > 0.05). In contrast, PHTPP-treated neurons had a significant loss of dendritic F-actin puncta compared to controls (p ≤ 0.05) and were not significantly different from HIV-1 Tat + cocaine treated dendrites (p > 0.05), indicating that PHTPP inhibited RE-induced synaptic protection. Mean ± SEM, ∗p ≤ 0.05. (B) HIV-1 Tat + cocaine exposed neurons pre-treated with either MPP or G15, and subsequently SE, had normal levels of dendritic F-actin puncta (i.e., not significantly different from vehicle-treated controls, p > 0.05). In contrast, PHTPP-treated neurons had a significant loss of dendritic F-actin puncta compared to controls (p ≤ 0.05) and were not significantly different from HIV-1 Tat + cocaine treated dendrites (p > 0.05), indicating that PHTPP inhibited SE-induced synaptic protection. Mean ± SEM, ∗p ≤ 0.05. (C–J) The ERβ antagonist PHTPP significantly blocked equol-mediated protection from HIV-1 Tat + cocaine in cortical neurons. PHTPP pre-treated, SE(I)/RE(J) treated, neurons lacked a fine dendritic network and had reduced dendritic branching, similar characteristics to those in non pre-treated HIV-1Tat + cocaine neurons (D). In contrast, vehicle (C), HIV-1 Tat (10 nM; G), cocaine (H), and SE(E)/RE(F) treated neurons had robust dendrites with complex branching patterns and a lack of aberrant morphology such as bundling or beading. Phalloidin/F-actin(green) and MAP-2 (blue); 20× magnification.

Mentions: Cortical neurons were treated with one of three selective ER subtype antagonists, MPP (ERα), PHTPP (ERβ), or G15 (GPR30) for 1 h prior to treatment with RE or SE in order to identify the specific ER subtype required for equol-mediated synaptic protection following HIV-1 Tat + cocaine (Figures 3A,B). There was a significant main effect of antagonist treatment F(3,134) = 11.2, p ≤ 0.001. Further analysis revealed that both the MPP, as well as the G15, treated dendrites were not significantly different from vehicle-treated controls (p > 0.05); however, PHTPP-treated dendrites had a significant loss of F-actin puncta when compared to controls (p ≤ 0.05) and were not significantly different from HIV-1 Tat + cocaine treated dendtrites (p > 0.05). More specifically, only the ERβ antagonist PHTPP significantly prevented RE or SE mediated synaptic protection (p ≤ 0.001), indicative of an ERβ dependent mechanism. Examination of either vehicle (Figure 3C), HIV-1 Tat (10 nM; Figure 3G), cocaine (Figure 3H), or SE (Figure 3E)/RE (Figure 3F) pre-treated neurons found robust staining of dendrites with Phalloidin/F-actin (green) puncta and MAP-2 (blue) dendrites. These neurons exhibited complex dendritic branching patterns and an extensive fine dendritic network. In contrast, examination of PHTPP pre-treated SE/HIV-1 Tat + cocaine treated (Figure 3I), PHTPP pre-treated RE/HIV-1 Tat + cocaine treated (Figure 3J), and HIV-1 Tat + cocaine treated (Figure 3D) neurons found reduced dendritic branching, diminished Phalloidin staining, and dendritic fragmentation.


HIV-1 Tat and cocaine mediated synaptopathy in cortical and midbrain neurons is prevented by the isoflavone Equol.

Bertrand SJ, Hu C, Aksenova MV, Mactutus CF, Booze RM - Front Microbiol (2015)

R-Equol and SE prevented HIV-1 Tat + cocaine synaptic loss via a selective estrogen receptor (ERβ) dependent mechanism. Cortical neurons were pre-treated for 1 h with either MPP (ERα), PHTPP (ERβ), or G15 (GPR30) prior to treatment with either RE (A) or SE (B) to identify which specific ER subtype was necessary for equol-mediated synaptic protection from HIV-1 Tat + cocaine. We found that pre-treatment with PHTPP (ERβ) inhibited both the RE (panel A) and SE (panel B) induced synaptic protection in HIV-1 Tat + cocaine treated cortical neurons. (A) HIV-1 Tat + cocaine exposed neurons pre-treated with either MPP or G15, and subsequently RE, had normal levels of dendritic F-actin puncta (i.e., not significantly different from vehicle-treated controls, p > 0.05). In contrast, PHTPP-treated neurons had a significant loss of dendritic F-actin puncta compared to controls (p ≤ 0.05) and were not significantly different from HIV-1 Tat + cocaine treated dendrites (p > 0.05), indicating that PHTPP inhibited RE-induced synaptic protection. Mean ± SEM, ∗p ≤ 0.05. (B) HIV-1 Tat + cocaine exposed neurons pre-treated with either MPP or G15, and subsequently SE, had normal levels of dendritic F-actin puncta (i.e., not significantly different from vehicle-treated controls, p > 0.05). In contrast, PHTPP-treated neurons had a significant loss of dendritic F-actin puncta compared to controls (p ≤ 0.05) and were not significantly different from HIV-1 Tat + cocaine treated dendrites (p > 0.05), indicating that PHTPP inhibited SE-induced synaptic protection. Mean ± SEM, ∗p ≤ 0.05. (C–J) The ERβ antagonist PHTPP significantly blocked equol-mediated protection from HIV-1 Tat + cocaine in cortical neurons. PHTPP pre-treated, SE(I)/RE(J) treated, neurons lacked a fine dendritic network and had reduced dendritic branching, similar characteristics to those in non pre-treated HIV-1Tat + cocaine neurons (D). In contrast, vehicle (C), HIV-1 Tat (10 nM; G), cocaine (H), and SE(E)/RE(F) treated neurons had robust dendrites with complex branching patterns and a lack of aberrant morphology such as bundling or beading. Phalloidin/F-actin(green) and MAP-2 (blue); 20× magnification.
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Figure 3: R-Equol and SE prevented HIV-1 Tat + cocaine synaptic loss via a selective estrogen receptor (ERβ) dependent mechanism. Cortical neurons were pre-treated for 1 h with either MPP (ERα), PHTPP (ERβ), or G15 (GPR30) prior to treatment with either RE (A) or SE (B) to identify which specific ER subtype was necessary for equol-mediated synaptic protection from HIV-1 Tat + cocaine. We found that pre-treatment with PHTPP (ERβ) inhibited both the RE (panel A) and SE (panel B) induced synaptic protection in HIV-1 Tat + cocaine treated cortical neurons. (A) HIV-1 Tat + cocaine exposed neurons pre-treated with either MPP or G15, and subsequently RE, had normal levels of dendritic F-actin puncta (i.e., not significantly different from vehicle-treated controls, p > 0.05). In contrast, PHTPP-treated neurons had a significant loss of dendritic F-actin puncta compared to controls (p ≤ 0.05) and were not significantly different from HIV-1 Tat + cocaine treated dendrites (p > 0.05), indicating that PHTPP inhibited RE-induced synaptic protection. Mean ± SEM, ∗p ≤ 0.05. (B) HIV-1 Tat + cocaine exposed neurons pre-treated with either MPP or G15, and subsequently SE, had normal levels of dendritic F-actin puncta (i.e., not significantly different from vehicle-treated controls, p > 0.05). In contrast, PHTPP-treated neurons had a significant loss of dendritic F-actin puncta compared to controls (p ≤ 0.05) and were not significantly different from HIV-1 Tat + cocaine treated dendrites (p > 0.05), indicating that PHTPP inhibited SE-induced synaptic protection. Mean ± SEM, ∗p ≤ 0.05. (C–J) The ERβ antagonist PHTPP significantly blocked equol-mediated protection from HIV-1 Tat + cocaine in cortical neurons. PHTPP pre-treated, SE(I)/RE(J) treated, neurons lacked a fine dendritic network and had reduced dendritic branching, similar characteristics to those in non pre-treated HIV-1Tat + cocaine neurons (D). In contrast, vehicle (C), HIV-1 Tat (10 nM; G), cocaine (H), and SE(E)/RE(F) treated neurons had robust dendrites with complex branching patterns and a lack of aberrant morphology such as bundling or beading. Phalloidin/F-actin(green) and MAP-2 (blue); 20× magnification.
Mentions: Cortical neurons were treated with one of three selective ER subtype antagonists, MPP (ERα), PHTPP (ERβ), or G15 (GPR30) for 1 h prior to treatment with RE or SE in order to identify the specific ER subtype required for equol-mediated synaptic protection following HIV-1 Tat + cocaine (Figures 3A,B). There was a significant main effect of antagonist treatment F(3,134) = 11.2, p ≤ 0.001. Further analysis revealed that both the MPP, as well as the G15, treated dendrites were not significantly different from vehicle-treated controls (p > 0.05); however, PHTPP-treated dendrites had a significant loss of F-actin puncta when compared to controls (p ≤ 0.05) and were not significantly different from HIV-1 Tat + cocaine treated dendtrites (p > 0.05). More specifically, only the ERβ antagonist PHTPP significantly prevented RE or SE mediated synaptic protection (p ≤ 0.001), indicative of an ERβ dependent mechanism. Examination of either vehicle (Figure 3C), HIV-1 Tat (10 nM; Figure 3G), cocaine (Figure 3H), or SE (Figure 3E)/RE (Figure 3F) pre-treated neurons found robust staining of dendrites with Phalloidin/F-actin (green) puncta and MAP-2 (blue) dendrites. These neurons exhibited complex dendritic branching patterns and an extensive fine dendritic network. In contrast, examination of PHTPP pre-treated SE/HIV-1 Tat + cocaine treated (Figure 3I), PHTPP pre-treated RE/HIV-1 Tat + cocaine treated (Figure 3J), and HIV-1 Tat + cocaine treated (Figure 3D) neurons found reduced dendritic branching, diminished Phalloidin staining, and dendritic fragmentation.

Bottom Line: In addition, the synapse-protective effects of either R-Equol (RE) or S-Equol (SE; derivatives of the soy isoflavone, daidzein) were determined.Individually, neither low concentrations of HIV-1 Tat (10 nM) nor low concentrations of cocaine (1.6 μM) had any significant effect on F-actin puncta number; however, the same low concentrations of HIV-1 Tat + cocaine in combination significantly reduced dendritic synapses.This synaptic reduction was prevented by pre-treatment with either RE or SE, in an estrogen receptor beta dependent manner.

View Article: PubMed Central - PubMed

Affiliation: Laboratory Program in Behavioral Neuroscience, Department of Psychology, University of South Carolina Columbia, SC, USA.

ABSTRACT
Illicit drugs, such as cocaine, are known to increase the likelihood and severity of HIV-1 associated neurocognitive disorders (HAND). In the current studies synaptic integrity was assessed following exposure to low concentrations of the HIV-1 viral protein Tat 1-86B, with or without cocaine, by quantifying filamentous actin (F-actin) rich structures (i.e., puncta and dendritic spines) on neuronal dendrites in vitro. In addition, the synapse-protective effects of either R-Equol (RE) or S-Equol (SE; derivatives of the soy isoflavone, daidzein) were determined. Individually, neither low concentrations of HIV-1 Tat (10 nM) nor low concentrations of cocaine (1.6 μM) had any significant effect on F-actin puncta number; however, the same low concentrations of HIV-1 Tat + cocaine in combination significantly reduced dendritic synapses. This synaptic reduction was prevented by pre-treatment with either RE or SE, in an estrogen receptor beta dependent manner. In sum, targeted therapeutic intervention with SE may prevent HIV-1 + drug abuse synaptopathy, and thereby potentially influence the development of HAND.

No MeSH data available.


Related in: MedlinePlus