a good pharmaceutical target for neurodegenerative disease treatment. It has been demonstrated that the neurological system is impacted by aluminium, arsenic, cadmium, lead, manganese, mercury, nitric oxide, cobalt, copper, calcium, lithium, iron, nickel, bismuth, selenium, and zinc. The degree of the immune response in the brain required to successfully manage infections without leading to neuropathology is still unknown—heavy-metal-produced neurotoxic activity, indicating the important participation of mitochondrial dysfunction triggered cell death.As a result, performs a key anti-inflammatory role by reducing microglial activation and supporting a well-regulated immune response, which is lacking during the pathophysiology of Neurotoxicity.

1. Metal Ion Neurotoxicity – Role of
Pro-Inflammatory Mediators
Priya Malik*
Priya Malik
M.Pharm (pharmacology)
Department of pharmacology
School of Medical and Allied Sciences
G.D Goenka University
Gurugram, Haryana, India

2. Background
• Environmental exposure to neurotoxic metal ions and metalloids is a global health
concern affecting millions of people worldwide (Carmona, A., et al., 2021).
• Depending on the period of exposure over a lifetime, environmental metals affect
neurodevelopment, neurobehavior, cognition, or are involved in the etiology of
neurodegenerative diseases such as Alzheimer’s (AD) and Parkinson’s (PD) diseases.
• lead (Pb), mercury (Hg), and cadmium (Cd), and the metalloid arsenic (As), have been
listed among the ten chemicals of major public health concern by the World Health
Organization (WHO, 2020).
• Currently 18 metals and one metalloid (As) appear on the top 150 of National Priorities
List from the Agency for Toxic Substances and Disease Registry (ATSDR). The majority
of the metals are highly toxic, and exposure to them can result in severe consequences in
the occupational setting (Andrade, V. M., et al., 2018).
• They having particular concern due to the long-lasting and possibly irreversible nature of
their effects. The metal ions exposure can result in cognitive and behavioral deficits in
children.
• Neurotoxicological disorders such as autism, attention deficit disorder, mental
retardation, and cerebral palsy are common but dangerous as it can cause lifelong
disability. Metal ions generate toxic effects on different organs of body and by this
differently affect Humans ( Sankhla, M. S., et al., 2017).

3. Sources of Neurotoxicity
• The nervous system is one of the most important systems in the human body, and its
proper functioning is vital to overall health and well-being.
• However, exposure to certain substances can lead to neurotoxicity, a condition that
affects the nervous system and can lead to a wide range of symptoms and health issues.
• There are many sources of neurotoxicity, and identifying these sources is an important
step in reducing the risk of exposure and preventing the negative effects of neurotoxicity.

4. Through air/ and food intake
Mechanism of Neurotoxicity

5. Metal ions that causes neurotoxicity

6. • Cytokines are pleiotropic molecules with important roles in inflammatory responses.
Pro-inflammatory cytokines and neuroinflammation are important not only in
inflammatory responses but also in neurogenesis and neuroprotection.
• Neuroinflammation is closely associated with excessive oxidative stress (Zhang et al.,
2009). Recently, chronic microglial production of pro-inflammatory cytokines including
interleukins (IL-1 and IL-6), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) has
received considerable attention for its role in neurodegenerative disorders.
• SNS sympathetic nervous system releases the catecholamines norepinephrine (NE) and
epinephrine (Epi) which are thought to act directly on both microglia and peripheral
immune cells to regulate their activity.
• Although microglia have been implicated as the major producers of TNF-α in
neurodegenerative disorders and CNS insult, numerous studies have demonstrated that
astrocytes and neurons may also be a source of this pro-inflammatory cytokine.
• ROS can also operate as second messengers to control a number of downstream
signalling molecules, such as NF-κB, mitogen-activated protein kinase, and protein
kinase C
Role of Pro-Inflammatory Mediators
in Neurotoxicity

7. • Activation of the NADPH oxidase pathway in phagocytic cells, such as macrophages,
starts an intracellular ROS signalling pathway that can increase the production of
proinflammatory cytokines, like TNFα.
• NADPH oxidase is a significant producer of reactive oxygen species (ROS) in
neutrophils, contributing to both oxidative burst and cell signalling pathways.
According to recent research, β-amyloid peptide-induced microglial activation is
mediated by intracellular ROS, while β-amyloid-induced NF-κB activation and
interleukin-1β production are reduced when intracellular ROS is inhibited

8. CONCLUSION
Metal ions are important because they promote the formation of plaque or redox cycling,
which are two ways that they operate as mediators of neurotoxicity. They thus offer a good
pharmaceutical target for neurodegenerative disease treatment. It has been demonstrated
that the neurological system is impacted by aluminium, arsenic, cadmium, lead,
manganese, mercury, nitric oxide, cobalt, copper, calcium, lithium, iron, nickel, bismuth,
selenium, and zinc. The degree of the immune response in the brain required to
successfully manage infections without leading to neuropathology is still unknown. heavy-
metal-produced neurotoxic activity, indicating the important participation of mitochondrial
dysfunction triggered cell death. As a result, performs a key anti-inflammatory role by
reducing microglial activation and supporting a well-regulated immune response, which is
lacking during the pathophysiology of Neurotoxicity.

10. • Carmona, Asuncion, Stéphane Roudeau, and Richard Ortega. "Molecular mechanisms of
environmental metal neurotoxicity: a focus on the interactions of metals with synapse
structure and function." Toxics 9.9 (2021): 198.
• World Health Organization (WHO). Ten Chemicals of Public Health Concern. 2020.
Available online: https://www.who.int/news-room/photo-story/photo-story-detail/10-
chemicals-of-public-health-concern (accessed on 21 July 2021).
• Andrade, V. M., Aschner, M., & Marreilha Dos Santos, A. P. (2017). Neurotoxicity of metal
mixtures. Neurotoxicity of metals, 227-265.
• Sankhla, M. S., Sharma, K., & Kumar, R. (2017). Heavy metal causing neurotoxicity in
human health. International Journal of Innovative Research in Science. Engineering and
Technology, 6(5).
• Garza-Lombó, C., Posadas, Y., Quintanar, L., Gonsebatt, M. E., & Franco, R. (2018).
Neurotoxicity linked to dysfunctional metal ion homeostasis and xenobiotic metal
exposure: redox signaling and oxidative stress. Antioxidants & redox signaling, 28(18),
1669-1703.
• Sankhla, M. S., Sharma, K., & Kumar, R. (2017). Heavy metal causing neurotoxicity in
human health. International Journal of Innovative Research in Science. Engineering and
Technology, 6(5).
• Lansdown, A. B. G. (2007). Critical observations on the neurotoxicity of silver. Critical
reviews in toxicology, 37(3), 237-250.
References