L-α-Aminoadipic acid

Neuroinflammation is a contributory factor underlying the progressive nature of dopaminergic neuronal loss within the substantia nigra (SN) of Parkinson's disease (PD) patients, albeit the role of astrocytes in this process has been relatively unexplored to date. Here, we aimed to investigate the impact of midbrain astrocytic dysfunction in the pathophysiology of intra-nigral lipopolysaccharide (LPS)-induced experimental Parkinsonism in male Wistar rats via simultaneous co-injection of the astrocytic toxin L-alpha-aminoadipic acid (L-AAA). Simultaneous intra-nigral injection of L-AAA attenuated the LPS-induced loss of tyrosine hydroxylase-positive (TH+ ) dopamine neurons in the SNpc and suppressed the affiliated degeneration of TH+ dopaminergic nerve terminals in the striatum. L-AAA also repressed LPS-induced nigrostriatal dopamine depletion and provided partial protection against ensuing motor dysfunction. L-AAA abrogated intra-nigral LPS-induced glial fibrillary acidic protein-positive (GFAP+ ) reactive astrogliosis and attenuated the LPS-mediated increases in nigral S100β expression levels in a time-dependent manner, findings which were associated with reduced ionized calcium binding adaptor molecule 1-positive (Iba1+ ) microgliosis, thus indicating a role for reactive astrocytes in sustaining microglial activation at the interface of dopaminergic neuronal loss in response to an immune stimulus. These results indicate that midbrain astrocytic dysfunction restricts the development of dopaminergic neuropathology and motor impairments in rats, highlighting reactive astrocytes as key contributors in inflammatory associated degeneration of the nigrostriatal tract.

The hypothesis has been tested that the enantiomers of alpha-aminoadipic acid have different target effects; the L-isomer has both glio- and neurotoxic actions, while the DL-isomer has a gliospecific action in the CNS. Electrophysiological and morphological studies were carried out on the retina of the carp (Cyprinus carpio) for one to two months after intraocular injection with alpha-aminoadipic acids at various doses. Intracellular recording from horizontal cells and extracellular recording of spike discharges from ganglion cells in isolated retinal preparations were made from control and pretreated retinas at various intervals after intraocular injection with the enantiomers. In control retinas, application of 15 mM L-alpha-aminoadipic acid in the superfusate resulted in hyperpolarization of all horizontal cells and in a decrease in amplitude of their light responses (S-potentials). In the retinas pretreated with L-alpha-aminoadipic acid (8 mumol), low amplitude S-potentials were seen during an early phase 2-4 h after ocular injection, but the normal appearance of S-potentials was restored one day after injection. In control retinas, a brief period of iontophoretic application of L-alpha-aminoadipic acid resulted in a slight activation of the spontaneous spike firing of ganglion cells but a slight decrease in the rate of light-induced firing. In retinas pretreated with intraocular L-alpha-aminoadipic acid (4 mumol) 4 h prior to eye removal, however, light-induced spike discharges were abolished from nearly all spontaneously firing ganglion cells (greater than 90%). Their unresponsiveness to light stimuli lasted for more than two months after injection, and was accompanied by insensitivity to iontophoretically applied putative neurotransmitters.(ABSTRACT TRUNCATED AT 250 WORDS)

L-alpha-Aminoadipic acid is a lysine metabolite with neuroexcitatory properties, and has previously been shown to inhibit the production of the broad spectrum excitatory amino acid receptor antagonist kynurenic acid in brain tissue slices. The effects of L-alpha-aminoadipic acid on the levels of extracellular kynurenic acid were now studied by microdialysis in the dorsal hippocampus of freely moving rats. Application of L-alpha-aminoadipic acid through the microdialysis probe dose dependently decreased both the concentration of endogenous kynurenic acid and of kynurenic acid which was produced de novo from its bioprecursor L-kynurenine (500 microM applied through the probe). 500 microM L-alpha-aminoadipic acid lowered the kynurenic acid concentration in the dialysate by 47% and 28% with and without precursor loading, respectively, whereas D-alpha-aminoadipic acid was without effect. Co-administration of 500 microM L-alpha-aminoadipic acid with 50 microM veratridine, which by itself produces a substantial decrease in the levels of extracellular kynurenic acid, did not result in a further reduction in kynurenic acid concentrations. Extensive neuronal degeneration caused by an intrahippocampal injection of quinolinic acid (120 nmol) did not interfere with the effect of L-alpha-aminoadipic acid. Taken together, these data suggest that the effect of L-alpha-aminoadipic acid on extracellular kynurenic acid levels is likely due to its direct action on astrocytes, which are known to harbor kynurenic acid's biosynthetic enzyme, kynurenine aminotransferase. L-alpha-Aminoadipic acid may modulate kynurenic acid function in the brain and thus play a role in the pathogenesis of neurodegenerative and seizure disorders.