Iron and manganese-related CNS toxicity: mechanisms, diagnosis and treatment

Abstract

Introduction: Iron (Fe) and manganese (Mn) are essential nutrients for humans. They act as cofactors for a variety of enzymes. In the central nervous system (CNS), these two metals are involved in diverse neurological activities. Dyshomeostasis may interfere with the critical enzymatic activities, hence altering the neurophysiological status and resulting in neurological diseases. Areas covered: In this review, the authors cover the molecular mechanisms of Fe/Mn-induced toxicity and neurological diseases, as well as the diagnosis and potential treatment. Given that both Fe and Mn are abundant in the earth crust, nutritional deficiency is rare. In this review the authors focus on the neurological disorders associated with Mn and Fe overload. Expert commentary: Oxidative stress and mitochondrial dysfunction are the primary molecular mechanism that mediates Fe/Mn-induced neurotoxicity. Although increased Fe or Mn concentrations have been found in brain of patients, it remains controversial whether the elevated metal amounts are the primary cause or secondary consequence of neurological diseases. Currently, treatments are far from satisfactory, although chelation therapy can significantly decrease brain Fe and Mn levels. Studies to determine the primary cause and establish the molecular mechanism of toxicity may help to adapt more comprehensive and satisfactory treatments in the future.

Metal Chelation Therapy and Parkinson’s Disease: A Critical Review on the Thermodynamics of Complex Formation between Relevant Metal Ions and Promising or Established Drugs

“…The authors were not able to give a definite answer, but they observed that Fe dyshomeostasis occurs already at early PD onset, and that Fe should at least contribute to many aspects of neurodegeneration, in a way such that Fe might be proposed as a biomarker to detect for preclinical stages of NDs. Similarly, prudent conclusions have been drawn in another very recent review by Chen et al [42], where the authors found that it was unclear whether Fe and Mn are primary or secondary causes of neurodegeneration, as they found that neurodegeneration cannot be reversed if metal overload is removed. The question about the primary or secondary role of Cu and Zn was raised by Barnham and Bush [41] in their review.…”

“…Essential metal ions like Cu, Fe, Mn, and Zn are known to be involved in a large number of biochemical processes in the human brain [41,42], where they exert a structural (e.g., stabilizing configurations of macromolecules) or a functional role (e.g., being the active site of metalloenzymes). Both Cu and Fe can exist in vivo under two oxidation states, Cu(II) and Cu(I), Fe(III) and Fe(II), to allow biological systems activating and using O 2 for energy purposes.…”

“…A dyshomeostasis of Fe or Cu can therefore have a significant impact on ROS regulation. Also, high labile Mn levels have been reported to increase oxidative stress [42]. Labile Zn 2+ is more abundant in healthy brain cells, as it is released by neural activity at many central excitatory synapses [48], but still this metal ion was related to oxidative stress [49].…”

Serum iron, Magnesium, Copper, and Manganese Levels in Alcoholism: A Systematic Review

“…Studies are consistent in reporting an increased deposition of manganese in the brain of patients suffering from hepatic encephalopathy (HE) [63,64,65,66,67,68,69]. This is depicted in the form of hyperintense MRI signals, in particular in the region of the brain called the globus pallidus [70].…”

Impact of an increased exposure with manganese and nickel on pituitary hormones in women with ovarian polycystosis

“…Дані літератури свідчать про те, що токсичні ефекти марганцю пов'язані з дегенеративними змінами дофамінергічних нейронів. В основі цих процесів лежить марганець-індукована аутофагія (самопоглинання) за участю механізмів оксидативного стресу [12][13][14]. В результаті дегенеративних змін спостерігається зменшення секреції дофаміну.…”