Metallothionein 1+2 protect the CNS during neuroglial degeneration induced by 6‐aminonicotinamide

Abstract

6-Aminonicotinamide (6-AN) is a niacin antagonist, which leads to degeneration of gray matter astrocytes. Metallothionein 1+2 (MT-1+2) are neuroprotective factors in the central nervous system (CNS), and to determine the roles for MT after 6-AN, we have examined transgenic mice overexpressing MT-1 (TgMTI* mice) after an i.p. injection with 6-AN. In control mice injected with 6-AN, astrocytes in specific gray matter areas of the brainstem showed degeneration. Reactive astrocytes surrounded the degenerated areas, which were heavily infiltrated by macrophages and T lymphocytes. MT-1+2 expression was significantly decreased in the damaged brainstem areas, but it increased in reactive astrocytes surrounding these areas and also in infiltrating macrophages. The levels of oxidative stress, as determined by immunoreactivity for inducible nitric-oxide synthase (iNOS), malondialdehyde (MDA), and nitrotyrosine (NITT), and the number of terminal deoxynucleotidyl transferase [TdT]-mediated deoxyuridine triphosphate [dUTP]-digoxigenin nick end labeling-positive (TUNEL+), caspase-3+ apoptotic cells were significantly increased in the brainstem of normal mice after 6-AN. In the TgMTI* mice, the 6-AN-induced tissue damage was decreased in comparison to control mice, and they showed significantly reduced numbers of recruited macrophages and T lymphocytes, and a drastic reduction of oxidative stress and apoptotic cell death. In addition, the accompanying reactive astrogliosis was increased in the transgenic mice. To further study the potential protective role of MT, we administered intraperitoneally Zn-MT-2 to 6-AN-injected normal mice and found essentially the same results as those obtained in TgMTI* mice. Thus, we hereby report that endogenous MT-1 overexpression and exogenous MT-2 treatment have significant neuroprotective roles during CNS pathological conditions.

Peculiarities of the Molecular Structure and Functions of Metallothioneins in the Central Nervous System

“…The level of zinc per se can also play an important role in the control of apoptosis; a decrease of this index leads to suppression of the activity of calcium-activating endonuclease and apoptotic protease [58]. Consequences of injections of MTs (similar to those mentioned above) were observed in rats after administration of 6-aminonicotinamide [59,60].…”

“…Under such conditions, the synthesis of anti-inflammatory cytokines increases [49,50], angiogenesis is intensified, [58], the survival of neurons also increases, and the processes of recovery of tissues are improved [36][37][38][59][60][61][62][63][64].…”

Mercury-induced cognitive impairment in metallothionein-1/2 null mice

“…The primary functions of metallothioneins are to maintain homeostatic levels of essential metals and detoxify non-essential metals [16,23,30]. MT1 and MT2 protect the central nervous system from damage induced by interleukin 6, 6-aminonicotinamide, kainic acid and physical injury [4,10,33]. Studies using MT1/MT2-null mice have also shown that MT1 and MT2 protect cells from damage induced by oxidative stress [25].…”

Atrophy of Large Myelinated Axons in Metallothionein-I, II Knockout Mice

“…Since myelinated axons do not express MT-I and II, their protective functions may be directly or indirectly delivered by grey matter astrocytes (Chung and West, 2004). In a study where the degeneration of grey matter astrocytes was chemically (6-aminonicotinamide) induced, the brain stem motor nuclei and their cranial nerves were protected from cell death due to ROS by over-expression of MT-I in a transgenic mouse model (Penkowa et al, 2002).…”