NEUROSTEROIDOGENESIS AS THERAPEUTIC STRATEGY TO COMBAT HORMONAL DYSREGULATION IN HIV-1 PATIENTS

by Salahuddin Mohammed

Graduate Research Assistant, Paris Lab

School of Pharmacy, Division of Pharmacology
Schematic diagram of hypothalamus, pituitary, adrenal gland axis, the problems resulting from dysregulation of this axis leading to increased corticosterone , and the hypothetical use of TSPO (a protein that transports the substrate for making hormones, cholesterol, to the mitochondria) to initiate steroidogenesis thereby correcting the imbalance in corticosterone to reduce anxiety, depression, and other psychiatric complications.

Would you like to humor your stress levels? We bet you would!

Experiencing weight gain and chronic health issues-blame it on cortisol, the hormone produced by adrenal glands and the HPA (hypothalamus, pituitary gland & adrenal gland) axis controls its secretion.

Cortisol gained popularity as the essential hormone that triggers our fight-or-flight response or as the “death hormone.”

Now there is more to this hormone.

Cortisol is not always bad for our body. It is responsible for many essential functions. It acts as our internal timekeeping clock, also known as circadian rhythm. This circadian clock assists us with getting up toward the beginning of the day by increasing cortisol and diminishes as the night advances by permitting melatonin levels to increase in the body, which permits us to sleep.

Most importantly, it prepares our body for the “fight or flight” response by mobilizing the energy stores to fight the stressor. However, once the stressor is subsided, cortisol levels should decline, and our body goes back to normal. However, what happens when we are in a constant condition of stress? A few issues related with constant undeniable degrees of stress are anxiety, depression, lack of concentration, focus, attention and memory and energy, digestion and sleep problems, headaches and heart complications.

Nonetheless, these issues are connected to undeniable degrees of stress and not reliably significant degrees of cortisol. Low cortisol levels are related with a few medical problems, like Addison’s disease, which can cause: Fatigue, loss of hunger and weight, nausea, vomiting, muscle weakness and skin color changes.

The HPA axis (hypothalamus, pituitary, and adrenal glands) regulates cortisol levels. This body axis needs to work synchronously for our hormones to be at optimal levels.

How is this related to HIV?

The current antiretroviral drug regimen has come as relief for HIV infected patients as they live longer but these patients demonstrate neurological and neuroendocrine (HPA axis) dysfunction and we hypothesize that HPA axis dysfunction may contribute to the neurological deficits. HPA axis dysfunction is common in HIV infected patients wherein they demonstrate increased basal cortisol levels compared to normal population, oddly, despite increased cortisol their adrenal glands respond insufficiently when exposed to a stressor. Our lab is working to understand the underlying mechanisms for HPA dysfunction in a transgenic mouse model that has a specific gene, Tat, known to be at high levels in the brains of HIV-1 patients.  We are using this model to determine how to reduce excess cortisol which may increase vulnerability to other neuropsychiatric complications. Neurosteroids (steroids formed in brain) have shown to confer neuroprotection and modulate the hypothalamic-pituitary-adrenal (HPA) axis. Thus, we are exploring the capacity to boost neurosteroidogenesis via TSPO activation (rate limiting step for neurosteroidogenesis) or Allopregnanolone (potent allosteric GABAA receptor modulator) administration, as a therapeutic strategy to reduce HPA dysregulation and comorbid affective and stress-sensitive neuropsychiatric disorders.

  1. Salahuddin MF, Mahdi F, Sulochana SP, Paris JJ. HIV-1 Tat Protein Promotes Neuroendocrine Dysfunction Concurrent with the Potentiation of Oxycodone Psychomotor Effects in Female Mice. Viruses. 2021 Apr 30;13(5):813. doi:10.3390/v13050813. PMID: 33946474; PMCID: PMC8147167.
  2. Salahuddin MF, Mahdi F, Paris JJ. HIV-1 Tat Dysregulates the Hypothalamic-Pituitary-Adrenal Stress Axis and Potentiates Oxycodone-Mediated Psychomotor and Anxiety-Like Behavior of Male Mice. Int J Mol Sci. 2020;21(21):8212.
  3. Salahuddin MF, Qrareya AN, Mahdi F, Jackson D, Foster M, Vujanovic T, Box JG, Paris JJ. HIV-1 Tat protein and oxycodone dysregulate adrenal and gonadal endocrine axes and promote affective and cognitive dysfunction in Mice. Hormones and Behavior, 2020; 119:104649.
  4. Paris JJ, Liere P,  Kim S , Mahdi F , Buchanan ME , Qrareya AN,  Mohammed SF , Pianos A , Fernandez N , Shariat-Madar Z, Knapp PE , Schumacher M, Hauser KF. Physiological Allopregnanolone is Neuroprotective against Combined HIV-1 Tat and Morphine-Induced Neurotoxic and Psychomotor Effects. Neurobiology of Stress. 2020; 12: 100211.

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