Worsening of the Toxic Effects of (±)Cis-4,4′-DMAR Following Its Co-Administration with (±)Trans-4,4′-DMAR: Neuro-Behavioural, Physiological, Immunohistochemical and Metabolic Studies in Mice
Abstract
:1. Introduction
2. Results
2.1. Behavioural Studies
2.1.1. Physiological and Neuro-Behavioural Responses with (±)Cis-4,4′-DMAR
2.1.2. Physiological and Neuro-Behavioural Responses to (±)Trans-4,4′-DMAR
2.1.3. Physiological and Neuro-Behavioural Responses to the Concurrent (±)Cis-4,4′-DMAR + (±)Trans-4,4′-DMAR Administration
2.2. Results of Tissue Samples Collection
2.2.1. Histological Results
2.2.2. Immunohistochemical Results
2.3. Excretion Studies on Urine Samples
2.4. Physiological and Neuro-Behavioural Responses with (±)Cis-4,4′-DMAR + (±)Trans-4,4′-DMAR Co-Administration
3. Discussion
3.1. Psychomotor Agitation
3.2. Aggression
3.3. Hyperthermia, Sweating, Salivation
3.4. Convulsions and Lethality
3.5. Immunoistochemical Studies
4. Materials and Methods
4.1. Animals
4.2. Drug Preparation and Dose selection
4.3. Behavioural Studies: Physiological and Neuro-Behavioural Responses
4.4. Collection of Tissue Samples
4.4.1. Histological Procedure
4.4.2. Immunohistochemical Procedure
4.5. Excretion Studies on Urine Samples
4.5.1. Chemicals and Reagents
4.5.2. Dose and Sample Collection
4.5.3. Excretion Studies
4.6. Data and Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Ethical Statements
Abbreviations
4:4′-DMAR | 4,4′-Dimethylaminorex; 4-Methyl-5-(4-methylphenyl)-4,5-dihydrooxazol-2-amine |
4-MAR | 4-Methylaminorex; 4-Methyl-5-phenyl-4,5-dihydrooxazol-2-amine |
Aminorex | 5-phenyl-4,5-dihydro-1,3-oxazol-2-amine |
Smac | Second mitochondria-derived activator of caspases |
DIABLO | Direct IAP-binding protein with low PI |
NF-kB | Nuclear factor-kappa B |
8-OHdG | 8-Hydroxy-2′-deoxyguanosine |
iNOS | Inducible nitric oxide synthase |
NOX-2 | NADPH oxidases-2 |
NT | 3-nitrotyrosine |
HSP27 | Heat shock protein 27 |
HSP70 | Heat shock protein 70 |
HSP90 | Heat shock protein 90 |
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COMPOUND | cis-4,4’-DMAR | ||||||||
---|---|---|---|---|---|---|---|---|---|
Doses (mg/kg) | vehicle | 0.1 | 1 | 3 | 10 | 30 | 60 | ||
Psychomotor agitation | Frequency % (n° of mice) | - | - | - | 100% (6) | 100% (6) | 100% (6) | 100% (6) | |
Duration (min) | - | - | - | 54.2 ± 10.30 | 121.0 ± 12.35 a | 235.1 ± 15.25 ab | 280.1 ± 12.35 ab | ||
Latency (min) | - | - | - | 61.2 ± 6.30 | 28.2 ± 7.20 a | 3.2 ± 0.25 ab | 2.2 ± 0.15 ab | ||
Sweating | Frequency % (n° of mice) | - | - | - | - | - | 100% (6) | 100% (6) | |
Salivation | Frequency % (n° of mice) | - | - | - | - | - | 100% (6) | 50% (3) | |
Hyperthermia | Variation (Δ°C) | −0.28 ± 0.12 | −0.18 ± 0.14 | −0.22 ± 0.17 | −0.34 ± 0.22 | −0.41 ± 0.13 | 1.52 ± 0.11 c | 2.22 ± 0.12 c | |
Latency (min) | - | - | - | - | - | 25 ± 0.25 | 7.12 ± 0.23 d | ||
Aggressiveness | Spontaneus | Frequency % (n° of mice) | - | - | - | - | - | - | nd |
Stimulated | Frequency % (n° of mice) | - | - | - | - | 100% (6) | 100% (6) | nd | |
Score (n° of bites) | - | - | - | - | 6 ± 0.23 | 10 ± 0.23 b | nd | ||
Convulsion | Frequency % (n° of mice) | - | - | - | - | - | 50% (3) | 100% (6) | |
Episodes (n°) | - | - | - | - | - | 3.5 ± 0.5 | 2.0 ± 0.41 d | ||
Latency of first episode (sec) | - | - | - | - | - | 10.5 ± 1.5 | 8.25 ± 1.1 | ||
Duration of each episode (sec) | - | - | - | - | - | 4.86 ± 1.26 | 16.14 ± 3.2 d | ||
Lethality | Frequency % (n° of mice) | - | - | - | - | - | 50% (3) | 100% (6) | |
Time of death (min) | - | - | - | - | - | 59.3 ± 2.3 | 31.9 ± 5.6 d | ||
Surviving mice % (n° of mice) | - | - | - | - | - | 50% (3) | 0% (0) |
COMPOUND | trans-4,4’-DMAR | ||||
---|---|---|---|---|---|
Doses (mg/kg) | vehicle | 30 | 60 | ||
Psychomotor agitation | Frequency % (n° of mice) | - | - | - | |
Duration (min) | - | - | - | ||
Latency (min) | - | - | - | ||
Sweating | Frequency % (n° of mice) | - | - | - | |
Salivation | Frequency % (n° of mice) | - | - | - | |
Hyperthermia | Variation (Δ°C) | −0.28 ± 0.12 | −0.37 ± 0.13 | −0.35 ± 0.16 | |
Latency (min) | - | - | - | ||
Aggressiveness | Spontaneus | Frequency % (n° of mice) | - | - | - |
Stimulated | Frequency % (n° of mice) | - | - | - | |
Score (n° of bites) | - | - | - | ||
Convulsion | Frequency % (n° of mice) | - | - | - | |
Episodes (n°) | - | - | - | ||
Latency of first episode (sec) | - | - | - | ||
Duration of each episode (sec) | - | - | - | ||
Lethality | Frequency % (n° of mice) | - | - | - | |
Time of death (min) | - | - | - |
COMPOUND | cis-4,4’-DMAR | trans | (cis + trans)-4-4’DMAR | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Doses (mg/kg) | vehicle | 1 | 10 | 60 | 30 | 1 + 30 | 10 + 30 | 60 + 30 | ||
Psychomotor agitation | Frequency % (n° of mice) | - | - | 100% (6) | 100% (6) | - | 50% (3) | 100% (6) | 100% (6) | |
Duration (min) | - | - | 121.0 ± 12.35 | 220.1 ± 12.35 | - | 55.0 ± 5.0 | 185.5 ± 11.0 e | nd | ||
Latency (min) | - | - | 28.2 ± 7.20 | 2.2 ± 0.15 | - | 45.2 ± 5.20 | 6.2 ± 2.20 e | 0.45 ± 0.10 f | ||
Sweating | Frequency % (n° of mice) | - | - | - | 100% (6) | - | - | 33% (2) | 100% (6) | |
Salivation | Frequency % (n° of mice) | - | - | - | 50% (3) | - | - | 33% (2) | 50% (3) | |
Hyperthermia | Variation (Δ°C) | −0.28 ± 0.12 | −0.22 ± 0.17 | −0.41 ± 0.13 | 2.22 ± 0.12 | −0.37 ± 0.13 | −0.70 ± 0.15 | 1.6 ± 0.11 e | 2.25 ± 0.09 | |
Latency (min) | - | - | - | 7.12 ± 0.23 | - | - | 28.0 ± 0.21 | 5.0 ± 0.23 f | ||
Aggressiveness | Spontaneus | Frequency % (n° of mice) | - | - | - | nd | - | - | - | nd |
Stimulated | Frequency % (n° of mice) | - | - | 100% (6) | nd | - | - | 100% (6) | nd | |
Score (n° of bites) | - | - | 6 ± 0.23 | nd | - | - | 10 ± 0.05 e | nd | ||
Convulsion | Frequency % (n° of mice) | - | - | - | 100% (6) | - | - | - | 100% (6) | |
Episodes (n°) | - | - | - | 2.0 ± 0.41 | - | - | - | 1.0 ± 0.0 f | ||
Latency of first episode (sec) | - | - | - | 8.25 ± 1.1 | - | - | - | 6.67 ± 2.73 | ||
Duration of each episode (sec) | - | - | - | 16.14 ± 6.2 | - | - | - | 40.0 ± 5.0 f | ||
Lethality | Frequency % (n° of mice) | - | - | - | 100% (6) | - | - | - | 100% (6) | |
Time of death (min) | - | - | - | 31.9 ± 5.6 | - | - | - | 11.0 ± 3.9 f | ||
Surviving mice % (n° of mice) | - | - | - | 0% (0) | - | - | - | 0% (0) |
COMPOUND | cis-4,4’-DMAR | trans-4,4’-DMAR | (cis + trans)-4-4’DMAR | ||
---|---|---|---|---|---|
Doses (mg/kg) | 10 | 10 | 10+10 | ||
Psychomotoragitation | Frequency % (n° of mice) | 100% (4) | - | 100% (4) | |
Duration (min) | 125.0 ± 10.12 | - | 171.0 ± 9.25 e | ||
Latency (min) | 26.4 ± 6.25 | - | 8.0 ± 4.25 e | ||
Sweating | Frequency % (n° of mice) | - | - | - | |
Salivation | Frequency % (n° of mice) | - | - | - | |
Hyperthermia | Variation (Δ°C) | −0.21 ± 0.15 | −0.32 ± 0.1 | 1.58 ± 0.23 e | |
Latency (min) | - | - | 32.0 ± 2.45 | ||
Aggressiveness | Spontaneus | Frequency % (n° of mice) | - | - | - |
Stimulated | Frequency % (n° of mice) | 100% (4) | - | 100% (4) | |
Score (n° of bites) | 5 ± 0.23 | - | 8 ± 0.13 e | ||
Convulsion | Frequency % (n° of mice) | - | - | - | |
Episodes (n°) | - | - | - | ||
Latency of first episode (sec) | - | - | - | ||
Duration of each episode (sec) | - | - | - | ||
Lethality | Frequency % (n° of mice) | - | - | - | |
Time of death (min) | - | - | - |
Mouse Dose (mg/kg) | HED | Human Dose | Human Dosage | Effects |
---|---|---|---|---|
(mg/kg) | (mg) | |||
0.1 | 0.0081 | 0.486 | Low | high state of vigilance, euphoria, decreased appetite, increased frequency of heartbeat and motor activity |
1 | 0.081 | 4.86 | ||
3 | 0.243 | 14.58 | ||
10 | 0.81 | 48.6 | Intermediate | restlessness, agitation and insomnia |
30 | 2.43 | 145.8 | high | involve severe anorexia, mild paranoia (sometimes hallucinations), hyperthermia, bruxism, facial spasms, an increase in aggression and desire for violence, seizures, an increased heart rate that will be involved in a cardiac arrest |
60 | 4.86 | 291.6 |
Marker | Dilution | Retrieval | |
---|---|---|---|
HSP27 | Santa Cruz Biotechnology, Inc. | 1:50 | HIER (0.25 mM EDTA buffer ) |
HSP70 | Santa Cruz Biotechnology, Inc. | 1:50 | HIER (0.25 mM EDTA buffer ) |
HSP90 | Santa Cruz Biotechnology, Inc. | 1:50 | HIER (0.25 mM EDTA buffer ) |
SMAC | Santa Cruz Biotechnology, Inc. | 1:100 | HIER (0.01 M citrate buffer) |
NF-kB | Santa Cruz Biotechnology, Inc. | 1:50 | HIER (0.25 mM EDTA buffer ) |
iNOS | Santa Cruz Biotechnology, Inc. | 1:100 | HIER (0.01 M citrate buffer) |
NOX-2 | Proteintech | 1:100 | HIER (0.01 M citrate buffer) |
NT | Santa Cruz Biotechnology, Inc. | 1:600 | HIER (0.01 M citrate buffer) |
8OHDG | Santa Cruz Biotechnology, Inc. | 1:500 | HIER (0.01 M citrate buffer) |
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Tirri, M.; Frisoni, P.; Bilel, S.; Arfè, R.; Trapella, C.; Fantinati, A.; Corli, G.; Marchetti, B.; De-Giorgio, F.; Camuto, C.; et al. Worsening of the Toxic Effects of (±)Cis-4,4′-DMAR Following Its Co-Administration with (±)Trans-4,4′-DMAR: Neuro-Behavioural, Physiological, Immunohistochemical and Metabolic Studies in Mice. Int. J. Mol. Sci. 2021, 22, 8771. https://doi.org/10.3390/ijms22168771
Tirri M, Frisoni P, Bilel S, Arfè R, Trapella C, Fantinati A, Corli G, Marchetti B, De-Giorgio F, Camuto C, et al. Worsening of the Toxic Effects of (±)Cis-4,4′-DMAR Following Its Co-Administration with (±)Trans-4,4′-DMAR: Neuro-Behavioural, Physiological, Immunohistochemical and Metabolic Studies in Mice. International Journal of Molecular Sciences. 2021; 22(16):8771. https://doi.org/10.3390/ijms22168771
Chicago/Turabian StyleTirri, Micaela, Paolo Frisoni, Sabrine Bilel, Raffaella Arfè, Claudio Trapella, Anna Fantinati, Giorgia Corli, Beatrice Marchetti, Fabio De-Giorgio, Cristian Camuto, and et al. 2021. "Worsening of the Toxic Effects of (±)Cis-4,4′-DMAR Following Its Co-Administration with (±)Trans-4,4′-DMAR: Neuro-Behavioural, Physiological, Immunohistochemical and Metabolic Studies in Mice" International Journal of Molecular Sciences 22, no. 16: 8771. https://doi.org/10.3390/ijms22168771
APA StyleTirri, M., Frisoni, P., Bilel, S., Arfè, R., Trapella, C., Fantinati, A., Corli, G., Marchetti, B., De-Giorgio, F., Camuto, C., Mazzarino, M., Gaudio, R. M., Serpelloni, G., Schifano, F., Botrè, F., & Marti, M. (2021). Worsening of the Toxic Effects of (±)Cis-4,4′-DMAR Following Its Co-Administration with (±)Trans-4,4′-DMAR: Neuro-Behavioural, Physiological, Immunohistochemical and Metabolic Studies in Mice. International Journal of Molecular Sciences, 22(16), 8771. https://doi.org/10.3390/ijms22168771