Richard E. Heikkila

Bio: Richard E. Heikkila is an academic researcher from University of Medicine and Dentistry of New Jersey. The author has contributed to research in topics: MPTP & Dopamine. The author has an hindex of 44, co-authored 101 publications receiving 9105 citations. Previous affiliations of Richard E. Heikkila include Rutgers University & Eli Lilly and Company.

Dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine in mice

Abstract: 1-Methyl-4-phenyl-1,2,5,6- tetrahydropyri dine ( MPTP ) is known to cause an irreversible destruction of the dopaminergic nigrostriatal pathway and symptoms of parkinsonism in humans and in monkeys. However, MPTP has been reported to act only minimally or not at all in several other animal species. When MPTP (30 milligrams per kilogram of body weight) was administered parenterally to mice, a decrease in concentrations of neostriatal dopamine and its metabolites, a decrease in the capacity of neostriatal synaptosomal preparations to accumulate [3H]dopamine, and a disappearance of nerve cells in the zona compacta of the substantia nigra were observed. In contrast, MPTP administration had no effect on neostriatal concentrations of serotonin and its metabolites. MPTP administration thus results in biochemical and histological changes in mice similar to those reported in humans and monkeys and similar to those seen in Parkinson's disease in humans. The mouse should prove to be a useful small animal with which to study the mode of action of MPTP .

Protection against the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine by monoamine oxidase inhibitors.

Abstract: 1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) causes degeneration of the dopaminergic nigrostriatal pathway in several animal species, including humans1,2, monkeys3,4 and mice5–7. Changes observed after MPTP administration include marked decrements in the neostriatal content of dopamine and its major metabolites, dihydroxyphenylacetic acid and homovanillic acid, and a greatly diminished capacity of neostriatal synaptosomes to take up 3H-dopamine5,6. In contrast, there is no pronounced loss of serotonin in the neostriatum or of dopamine and its metabolites in other brain areas in MPTP-treated animals. The oxidative metabolism of MPTP to 1-methyl-4-phenyl pyridine, a positively charged species, has been suggested as a critical feature in the neurotoxic process8. Moreover, in rat brain preparations, the monoamine oxidase (MAO) inhibitor pargyline and the specific MAO-B inhibitor deprenil can prevent the formation of 1-methyl-4-phenyl-pyridine from MPTP, while the specific MAO-A inhibitor clorgyline has no such effect9, suggesting that MAO, and specifically MAO-B, is responsible for the oxidative metabolism of MPTP. We now report that pargyline, nialamide and tranylcypromine, which inhibit both MAO-A and MAO-B, when administered to mice before MPTP, protect against MPTP-induced dopaminergic neurotoxicity. Deprenil is also protective, but clorgyline is not. Our data are consistent with the premise that MAO-B has a crucial role in MPTP-induced degeneration of the nigrostriatal dopaminergic neuronal pathway.

Role for excitatory amino acids in methamphetamine-induced nigrostriatal dopaminergic toxicity

Abstract: The systemic administration of either methamphetamine or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to experimental animals produces degenerative changes in nigrostriatal dopaminergic neurons or their axon terminals. This study was conducted to determine if excitatory amino acids, which appear to be involved in various neurodegenerative disorders, might also contribute to the dopaminergic neurotoxicity produced in mice by either methamphetamine or MPTP. MK-801, phencyclidine, and ketamine, noncompetitive antagonists of one subtype of excitatory amino acid receptor, the N-methyl-D-aspartate receptor, provided substantial protection against neurotoxicity produced by methamphetamine but not that produced by MPTP. These findings indicate that excitatory amino acids play an important role in the nigrostriatal dopaminergic damage induced by methamphetamine.

Oxidative stress, glutamate, and neurodegenerative disorders

Abstract: There is an increasing amount of experimental evidence that oxidative stress is a causal, or at least an ancillary, factor in the neuropathology of several adult neurodegenerative disorders, as well as in stroke, trauma, and seizures. At the same time, excessive or persistent activation of glutamate-gated ion channels may cause neuronal degeneration in these same conditions. Glutamate and related acidic amino acids are thought to be the major excitatory neurotransmitters in brain and may be utilized by 40 percent of the synapses. Thus, two broad mechanisms--oxidative stress and excessive activation of glutamate receptors--are converging and represent sequential as well as interacting processes that provide a final common pathway for cell vulnerability in the brain. The broad distribution in brain of the processes regulating oxidative stress and mediating glutamatergic neurotransmission may explain the wide range of disorders in which both have been implicated. Yet differential expression of components of the processes in particular neuronal systems may account for selective neurodegeneration in certain disorders.

Chronic systemic pesticide exposure reproduces features of Parkinson's disease

Abstract: The cause of Parkinson's disease (PD) is unknown, but epidemiological studies suggest an association with pesticides and other environmental toxins, and biochemical studies implicate a systemic defect in mitochondrial complex I. We report that chronic, systemic inhibition of complex I by the lipophilic pesticide, rotenone, causes highly selective nigrostriatal dopaminergic degeneration that is associated behaviorally with hypokinesia and rigidity. Nigral neurons in rotenone-treated rats accumulate fibrillar cytoplasmic inclusions that contain ubiquitin and alpha-synuclein. These results indicate that chronic exposure to a common pesticide can reproduce the anatomical, neurochemical, behavioral and neuropathological features of PD.

Dopamine Receptors: From Structure to Function

Abstract: Missale, Cristina, S. Russel Nash, Susan W. Robinson, Mohamed Jaber, and Marc G. Caron. Dopamine Receptors: From Structure to Function. Physiol. Rev. 78: 189–225, 1998. — The diverse physiological actions of dopamine are mediated by at least five distinct G protein-coupled receptor subtypes. Two D1-like receptor subtypes (D1 and D5) couple to the G protein Gs and activate adenylyl cyclase. The other receptor subtypes belong to the D2-like subfamily (D2 , D3 , and D4) and are prototypic of G protein-coupled receptors that inhibit adenylyl cyclase and activate K+ channels. The genes for the D1 and D5 receptors are intronless, but pseudogenes of the D5 exist. The D2 and D3 receptors vary in certain tissues and species as a result of alternative splicing, and the human D4 receptor gene exhibits extensive polymorphic variation. In the central nervous system, dopamine receptors are widely expressed because they are involved in the control of locomotion, cognition, emotion, and affect as well as neuroendocrine s...

Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1

Abstract: Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra We previously mapped a locus for a rare familial form of PD to chromosome 1p36 (PARK6) Here we show that mutations in PINK1 (PTEN-induced kinase 1) are associated with PARK6 We have identified two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families: a truncating nonsense mutation and a missense mutation at a highly conserved amino acid Cell culture studies suggest that PINK1 is mitochondrially located and may exert a protective effect on the cell that is abrogated by the mutations, resulting in increased susceptibility to cellular stress These data provide a direct molecular link between mitochondria and the pathogenesis of PD