Sulforaphane and Brain Health: From Pathways of Action to Effects on Specific Disorders

Abstract

The brain accounts for about 2% of the body's weight, but it consumes about 20% of the body's energy at rest, primarily derived from ATP produced in mitochondria. The brain thus has a high mitochondrial density in its neurons because of its extensive energy demands for maintaining ion gradients, neurotransmission, and synaptic activity. The brain is also extremely susceptible to damage and dysregulation caused by inflammation (neuroinflammation) and oxidative stress. Many systemic challenges to the brain can be mitigated by the phytochemical sulforaphane (SF), which is particularly important in supporting mitochondrial function. SF or its biogenic precursor glucoraphanin, from broccoli seeds or sprouts, can confer neuroprotective and cognitive benefits via diverse physiological and biochemical mechanisms. SF is able to cross the blood-brain barrier as well as to protect it, and it mitigates the consequences of destructive neuroinflammation. It also protects against the neurotoxic effects of environmental pollutants, combats the tissue and cell damage wrought by advanced glycation end products (detoxication), and supports healthy glucose metabolism. These effects are applicable to individuals of all ages, from the developing brains in periconception and infancy, to cognitively, developmentally, and traumatically challenged brains, to those in later life as well as those who are suffering with multiple chronic conditions including Parkinson's and Alzheimer's diseases.

Keywords: autism; broccoli; cognition; detoxication; glucoraphanin; neurologic; nutrition; psychiatric; schizophrenia.

Figure 1

Human brain development. Sequential development of targeted neural pathways (synaptogenesis): First sensory (vision and hearing) synapse formation in the visual and auditory cortex, then language in the angular gyrus of the parietal lobe and speech production Broca’s area in the frontal lobe, then higher cognitive function in the prefrontal cortex. (Redrawn from [1]).

Figure 2

Glucoraphanin, myrosinase, and sulforaphane. Glucoraphanin is the biogenic, stable, and relatively non-biologically reactive glucosinolate precursor of sulforaphane. Glucoraphanin is converted to sulforaphane by myrosinase (E.C. 3.2.147), an enzyme not produced by humans, but present in their intestinal microbiome, as well as in each of the many thousand plant species that contain glucosinolates.

Figure 3

Sulforaphane and the brain. Sulforaphane has been shown experimentally and in many preclinical and clinical studies to act on a variety of pathways of cognition and brain health (left side), resulting in gradations of symptom amelioration, relief, or prevention of a variety of seemingly unrelated disorders and conditions (right side). In cases where cause and effect can be ascribed, pathways on the left side of this diagram have been linked to the effects of sulforaphane on those conditions by molecular, enzymatic, biomarker, or other biochemical evidence.

Figure 4

Structure of the blood–brain barrier (BBB). The BBB is composed of several cell types; the smooth muscle cells are present in vessels with higher diameters, astrocytes bind to the vessel through their feet, and pericytes enclose the vessel and are surrounded by a basement membrane. The endothelial cells are tightly bound together through several cell junction proteins, which include claudin and occludin that in turn connect to the actin cytoskeleton through zonulin, VE-Cadherin, and other permeability-modulating proteins (adapted from Cazalla 2024; ref. [25]).

Figure 5

Major biochemical pathways that are affected by sulforaphane (SF). (A) SF upregulates the Nrf2 pathway via its binding to the chaperone protein Keap1, with attendant interactions with mitochondria; (B) SF inhibits the NF-кB pathway through its interaction with IкK or cysteine residues in NF-кB; (C) SF upregulates the heat shock proteins (HSP). (redrawn from Liu 2016; ref. [14]).

Figure 6

Indirect antioxidant strategy. Direct antioxidants like vitamins E (right side) and C act directly to neutralize reactive oxygen species (ROS) and reactive nitrogen species. Indirect antioxidants like SF (left side) are potent inducers of the cells’ antioxidant enzymes as well as the body’s most abundant endogenous antioxidant, glutathione (GSH), which together act to neutralize ROS and other oxidants. By virtue of the fact that these are enzymes (and GSH is continuously enzymatically re-reduced and made re-available), this effect of SF is long-lived (hours to days) as opposed to direct antioxidants, which are used up as soon as they act.

Figure 7

Interactions of sulforaphane and Nrf2 with the gamma-glutamyl (glutathione; GSH) cycle. Additional abbreviations used for clarity in this figure: Cys, cysteine; GR, glutathione reductase.