Before we discuss the exciting new discovery of cholesterol-based drugs, have you ever considered why your brain is white? It is because the brain synthesizes its own cholesterol through a process called de novo lipogenesis. The brain’s ability to produce cholesterol is essential because it cannot rely solely on cholesterol from the bloodstream due to the blood-brain barrier. The process primarily occurs in glial cells, particularly astrocytes.

The word cholesterol comes from Ancient Greek roots chole (bile) and stereos (solid) followed by ol (an alcohol). In 1769 François Poulletier de la Salle identified solid cholesterol in gallstones. It was later discovered that de novo lipogenesis in the brain is a process that primarily converts carbohydrates into fatty acids and lipids, including cholesterol.

First, an overview of the brain’s unique shades of color: The brain appears white in some areas and gray in others due to the presence of myelinated axons in the white matter. Myelin is a fatty substance that wraps around the axons of neurons. This insulation—the myelin sheath—helps speed up the transmission of electrical signals between neurons.

White Matter vs. Gray Matter

• White Matter contains myelinated axons, which give it a lighter color. It primarily facilitates communication between different brain regions.
• Gray Matter is composed of neuronal cell bodies, dendrites, and unmyelinated axons, giving it a darker appearance. Gray matter is involved in processing and integrating information.

The contrast between white and gray matter is important for understanding brain structure and function, with each playing distinct roles in how the brain processes information.

The Brain’s Cholesterol Factory

The process of brain cholesterol production starts with glucose, which can be converted into acetyl-CoA, the main building block for fatty acids. Glucose undergoes glycolysis, breaking down into pyruvate. Pyruvate is then transported into the mitochondria, where it’s converted into acetyl-CoA, and finally converted into fatty acids through a series of reactions involving enzymes known as fatty acid synthases. In addition to fatty acids, some of the acetyl-CoA is directed towards the mevalonate pathway, which ultimately leads to the synthesis of cholesterol.

Brain cholesterol is vital for building cell membranes, myelination of neurons, and supporting synaptic function. The process is crucial for maintaining the brain’s lipid balance and supporting structural, electrical, and functional integrity. Brain cholesterol plays a significant role in neuroplasticity, which is the brain’s ability to adapt and reorganize itself in response to experiences, learning, and injury. Cholesterol is involved in the growth and maintenance of synapses. It supports the assembly of lipid rafts—specialized microdomains in cell membranes that facilitate protein interactions and signaling pathways important for synaptic plasticity. Oxysterols, which are pale or colorless, are modulators of cholesterol metabolism and profoundly influence neuroplasticity, neurodegeneration, and cognitive functions. These effects help explain how the brain might respond to stress, inflammation, and injury.

Neurosteroid (Cholesterol-Based) Drugs

Neuroactive steroids are derived from cholesterol. Neurosteroids are synthesized in the brain and other tissues from cholesterol through a series of enzymatic reactions, leading to compounds like allopregnanolone and dehydroepiandrosterone (DHEA). So while they are related, neurosteroids are distinct molecules that play various roles in the nervous system.

The future of neurosteroids is exciting, with ongoing research exploring their promising roles in brain health and mental disorders. Brain receptors called GABA-A and glutamate receptors are involved in regulating anxiety, mood, and overall emotional stability. Dysregulation can contribute to disorders like anxiety, depression, and epilepsy. One new drug, zuranolone, is a neuroactive steroid medication that acts primarily as a positive allosteric modulator of GABA-A receptors. Here are some other points to consider:

• Mental health Treatments. Neurosteroids like allopregnanolone are being developed to treat anxiety, postpartum depression, and PTSD. Clinical trials are exploring how these compounds can enhance mood and emotional regulation.
• Neuroprotection. Neurosteroids may offer protective effects against neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. Research into their mechanisms could lead to new therapeutic strategies.
• Cognitive Enhancement. There’s interest in how neurosteroids might improve memory and cognitive function. This could have implications for aging populations and conditions like ADHD.
• Hormonal Regulation. Understanding how neurosteroids interact with hormones could lead to better treatments for hormonal imbalances and related disorders, particularly in women.
• Personalized Medicine. As research advances, there’s potential for personalized treatments based on individual neurosteroid profiles, leading to more effective and targeted therapies.
• Brexanolone and Zuranolone. The first breakthrough FDA-approved treatments for postpartum depression, which can also reduce anxiety and distress levels.
• Neuroactive steroids targeting GABA receptors. Various compounds are being designed to selectively modulate GABA-A receptor subtypes, with the aim of reducing anxiety and enhancing mood.

Scientists are just beginning to examine the mysterious gray and white substance that composes our brains. Functional brain imaging has also begun to uncover some of the brain circuitry influenced by neurosteroids. A better understanding of the brain’s unique cholesterol factory will allow the development of new drugs to offer hope for the treatment of depression, bipolar disorder, and seizure disorders as well as neurodegenerative diseases.