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Pharmacokinetic and Pharmacodynamic Properties of Indole-3-carbinol in Experimental Focal Ischemic Injury

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Abstract

Background and Objectives

Indole-3-carbinol (I3C) is reported to have neuroprotective properties in an animal model of ischemic stroke. However, the pharmacokinetics of I3C in stroke animals are unknown. Furthermore, the most effective method of I3C delivery for the treatment of stroke has yet to be determined. Therefore, the objective of this study was to evaluate pharmacokinetics and pharmacodynamics of I3C to discover the most effective delivery route for protecting the brain from ischemic injury.

Methods

With oral and intravenous administration, the pharmacokinetics and pharmacodynamics of I3C in sham and middle cerebral artery occluded (MCAO) rats were investigated.

Results

I3C administration in sham and MCAO rats did not alter the pharmacokinetic parameters such as maximum plasma concentration (Cmax), time to reach Cmax, half-life, area under the curve, mean residential time, volume of distribution, clearance, bioavailability, and tissue distribution. A higher amount of diindolylmethane (DIM) was observed with oral administration of I3C compared to intravenous administration in the plasma (5 fold), brain (4 fold), and cerebrospinal fluid (CSF) (2–3 fold). Orally delivered I3C significantly reduced neurological deficits, brain infarction (20%), blood-brain barrier leakage (15 μg/g), and brain water content (75%) in MCAO rats compared to intravenous administration of I3C.

Conclusions

I3C pharmacokinetic parameters were similar in sham and MCAO rats, but I3C and DIM penetration in the brain and CSF was significantly higher in MCAO rats than in sham animals, and I3C oral intake significantly reduced MCAO-induced neurological impairments. Consequently, compared to intravenous treatment, I3C oral delivery is more effective in treating ischemic stroke.

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Acknowledgments

Kakarla Ramakrishna thanks IIT (BHU), Varanasi, and MHRD, India, for providing the teaching assistantship for carrying out the experimental work. We also thank Pankaj Paliwal and Akanksha Mishra, research scholars of Pharmaceutical Engineering and Technology, IIT (BHU), Varanasi, India, for their help in the experiments.

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Authors and Affiliations

  1. Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, Banaras Hindu University (IIT BHU), Varanasi, Uttar Pradesh, India

    Kakarla Ramakrishna, Shreyans K. Jain & Sairam Krishnamurthy

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  1. Kakarla Ramakrishna
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  2. Shreyans K. Jain
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  3. Sairam Krishnamurthy
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Corresponding author

Correspondence to Sairam Krishnamurthy.

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The authors report no conflict of interest.

Ethics approval

The experimental protocol was approved by IMS, BHU, Varanasi (protocol no. Dean/2016/CAEC/31). The approved protocol strictly adhered to the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) and follows the ARRIVE guidelines.

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All data generated or analyzed during this study are included in this manuscript and also available in a supplementary file.

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KR designed and performed the experiment, analyzed the data, and wrote the manuscript. SKJ helped perform experiments and edited the manuscript. SK designed and analyzed the data and edited the manuscript.

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Ramakrishna, K., Jain, S.K. & Krishnamurthy, S. Pharmacokinetic and Pharmacodynamic Properties of Indole-3-carbinol in Experimental Focal Ischemic Injury. Eur J Drug Metab Pharmacokinet 47, 593–605 (2022). https://doi.org/10.1007/s13318-022-00771-y

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  • DOI: https://doi.org/10.1007/s13318-022-00771-y

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