Neuroprotective Effects of Black Pepper and Its Bioactive Compounds in Age-Related Neurological Disorders

Abstract

Age-related neurological disorders (ANDs), including neurodegenerative diseases, are multifactorial disorders whose risk increases with age. The main pathological hallmarks of ANDs include behavioral changes, excessive oxidative stress, progressive functional declines, impaired mitochondrial function, protein misfolding, neuroinflammation, and neuronal cell death. Recently, efforts have been made to overcome ANDs because of their increased age-dependent prevalence. Black pepper, the fruit of Piper nigrum L. in the family Piperaceae, is an important food spice that has long been used in traditional medicine to treat various human diseases. Consumption of black pepper and black pepper-enriched products is associated with numerous health benefits due to its antioxidant, antidiabetic, anti-obesity, antihypertensive, anti-inflammatory, anticancer, hepatoprotective, and neuroprotective properties. This review shows that black pepper's major bioactive neuroprotective compounds, such as piperine, effectively prevent AND symptoms and pathological conditions by modulating cell survival signaling and death. Relevant molecular mechanisms are also discussed. In addition, we highlight how recently developed novel nanodelivery systems are vital for improving the efficacy, solubility, bioavailability, and neuroprotective properties of black pepper (and thus piperine) in different experimental AND models, including clinical trials. This extensive review shows that black pepper and its active ingredients have therapeutic potential for ANDs.

Figure 1.

Hallmarks of brain aging. These include altered intercellular communication, stem-cell exhaustion, genomic instability, DNA damage, epigenetic changes, mitochondrial dysfunction, stress response, impaired protein quality control, deregulated nutrient sensing, and cellular senescence.

Figure 2.

Neuroprotective effects of black pepper and its constituent piperine in age-related neurological disorders. Black pepper affects AD, PD, HD, MS, ischemic stroke, and epilepsy through each underlying mechanism. Down-arrows (↓) and up-arrows (↑) indicate inhibition and activation by black-pepper treatment, respectively. Key: Aβ, amyloid beta; DA, dopamine; SOD, superoxide dismutase; HO-1, heme oxygenase; Nrf2, nuclear factor erythroid 2-related factor 2; GABA, γ-aminobutyric acid; TH, tyrosine hydroxylase.

Figure 3.

Black pepper and piperine nanoformulations pave the way for combating age-related neurological disorders, targeting different dysregulated mechanisms.

Figure 4.

Neuroprotective potential of black pepper and its bioactive compound piperine in age-related neurological disorders. Black pepper and piperine show various neuropharmacological effects via antioxidative stress, anti-neuroinflammation, cholinergic function, anti-Aβ toxicity, anti-neuronal apoptosis, and synaptic function modulation. The block lines () and arrows (→) denote inhibition and stimulation actions by black pepper and piperine, respectively. Key: Aβ, amyloid beta; HO-1, heme oxygenase; Nrf2, nuclear factor erythroid 2-related factor 2; NF-κB, nuclear factor kappa B; ROS, reactive oxygen species; iNOS, inducible nitric oxide synthase; COX-2, cyclooxygenase-2; LPS, lipopolysaccharide; AChE, acetylcholinesterase; IL-1β, interleukin-1β; TNF-α, tumor necrosis factor-α; IL-6, interleukin-6; PSD-95, postsynaptic density protein 95; GSH, glutathione; GPx, glutathione peroxidase; Bcl2, B-cell lymphoma 2.