Alterations of striatal glutamate transmission in rotenone-treated mice: MRI/MRS in vivo studies

Abstract

Animal models treated with agricultural chemicals, such as rotenone, reproduce several degenerative features of human central nervous system (CNS) diseases. Glutamate is the most abundant excitatory amino acid transmitter in the mammalian central nervous system and its transmission is implicated in a variety of brain functions including mental behavior and memory. Dysfunction of glutamate neurotransmission in the CNS has been associated with a number of human neurodegenerative diseases, either as a primary or as a secondary factor in the excitotoxic events leading to neuronal death. Since many human CNS disorders do not arise spontaneously in animals, characteristic functional changes have to be mimicked by toxic agents. Candidate environmental toxins bearing any direct or indirect effects on the pathogenesis of human disease are particularly useful. The present longitudinal Magnetic Resonance Imaging (MRI) studies show, for the first time, significant variations in the properties of brain ventricles in a rotenonetreated (2mg/kg) mouse model over a period of 4 weeks following 3 days of rotenone treatment. Histopathological analysis reveals death of stria terminalis neurons following this short period of rotenone treatment. Furthermore, in vivo voxel localized 1 H MR spectroscopy also shows for the first time significant bio-energetic and metabolic changes as well as temporal alterations in the levels of glutamate in the degenerating striatal region. These studies provide novel insights on the effects of environmental toxins on glutamate and other amino acid neurotransmitters in human neurodegenerative diseases.

Mitochondrial Dysfunction in Aging Rat Brain Regions upon Chlorpyrifos Toxicity and Cold Stress: An Interactive Study

“…It is clear from the present study that CPF exerts an imbalance in neuro-chemical homeostasis resulting in AChE inhibition (Tables 1, 2, 3, 4). The inhibition of AChE activity disturbs the metabolic and neuronal activities and also causes deformities of cell membrane (Moussa et al 2008). Decreased AChE activity observed following CPF exposure in the present study is in agreement with the earlier report (Moussa et al 2008), while decreased ChAT activity levels in this study on exposure to CPF could be related to changes in high affinity of choline uptake as a result of oxidative stress.…”

“…Activity of AChE is vital for the functioning of cholinergic system and represents a prime target on which some toxicants can exert a detrimental effect (Moussa et al 2008). Similarly, ChAT activity provides insight into the potential rate of ACh biosynthesis and is often used as a prototypical marker for functional cholinergic neurons (Moussa et al 2008). It is clear from the present study that CPF exerts an imbalance in neuro-chemical homeostasis resulting in AChE inhibition (Tables 1, 2, 3, 4).…”

“…CPF is bio-activated to its neurotoxic metabolite, CPF-Oxon, and elicits toxicity through inhibition of AChE. Activity of AChE is vital for the functioning of cholinergic system and represents a prime target on which some toxicants can exert a detrimental effect (Moussa et al 2008). Similarly, ChAT activity provides insight into the potential rate of ACh biosynthesis and is often used as a prototypical marker for functional cholinergic neurons (Moussa et al 2008).…”

“…Organophosphate (OP) compounds being potent acetylcholine esterase (AChE) inhibitors are shown to inhibit mitochondrial enzymes (Moussa et al 2008) and their exposure in non-target animals are shown to induce perturbations leading to death. Chlorpyrifos (CPF) toxicity has been largely associated with irreversible inhibition of AChE resulting in accumulation of ACh (Lukaszewicz-Hussain 2010;Eaton et al 2008).…”

Protective Effects of Curcumin Against Rotenone and Salsolinol-Induced Toxicity: Implications for Parkinson’s Disease

“…It has been suggested that salsolinol leads to neurotoxicity through inhibition of mitochondrial complex II (succinate-Q reductase) activity, and/or by initiating apoptotic processes by generating free radicals (Maruyama et al, 1995, Storch et al, 2000). Rotenone’s effect has been attributed to inhibition of mitochondrial complex I (Betarbet et al, 2000, Alam and Schmidt, 2002, Hoglinger et al, 2003), the release of NADPH oxidase-derived superoxide from activated microglia (Gao et al, 2002) and possibly alteration of glutamate transmission (Leng et al, 2003, Moussa et al, 2008). Both drugs might also cause inflammation, which appears to contribute to the formation of PD (Gao et al, 2003a,b, Zhang et al, 2011, Chinta et al, 2013).…”