Neuroprotective Activities of Palmitoylethanolamide in an Animal Model of Parkinson's Disease

Abstract

The biochemical and cellular changes that occur following treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine (MPTP) are remarkably similar to that seen in idiopathic Parkinson's disease (PD). PD is characterized by the degeneration of dopaminergic nigrostriatal neurons, which results in disabling motor disturbances. Activation of glial cells and the consequent neuroinflammatory response is increasingly recognized as a prominent neuropathological feature of PD. There is currently no effective disease-modifying therapy. Targeting the signaling pathways in glial cells responsible for neuroinflammation represents a promising new therapeutic approach designed to preserve remaining neurons in PD. Chronic treatment with palmitoylethanolamide (PEA, 10 mg/kg, i.p.), initiated 24 hr after MPTP injection (20 mg/kg), protected against MPTP-induced loss of tyrosine hydroxylase positive neurons in the substantia nigra pars compacta. Treatment with PEA reduced MPTP-induced microglial activation, the number of GFAP-positive astrocytes and S100β overexpression, and protected against the alterations of microtubule-associated protein 2a,b-, dopamine transporter-, nNOS- positive cells in the substantia nigra. Furthermore, chronic PEA reversed MPTP-associated motor deficits, as revealed by the analysis of forepaw step width and percentage of faults. Genetic ablation of peroxisome proliferator activated receptor (PPAR)-α in PPAR-αKO mice exacerbated MPTP systemic toxicity, while PEA-induced neuroprotection seemed be partially PPARα-dependent. The effects of PEA on molecules typically involved in apoptotic pathways were also analyzed. Our results indicate that PEA protects against MPTP-induced neurotoxicity and the ensuing functional deficits even when administered once the insult has been initiated.

The Neuroprotective Effect of Dimethyl Fumarate in an MPTP-Mouse Model of Parkinson's Disease: Involvement of Reactive Oxygen Species/Nuclear Factor-κB/Nuclear Transcription Factor Related to NF-E2

“…and then decapitated with large bandage scissors; their brains were harvested, sectioned, and processed. The dose of MPTP (20 mg/kg) used was based on previous in vivo studies (22), whereas doses of DMF were based on our previous colitis study (13) as well as on prior dose-response and timecourse studies in our laboratory. Experimental data regarding groups 2, 3, and 4 are related only to histological evaluation, as DMF administration did not result in either toxicity or improvement in comparison to sham controls (revised Fig.…”

“…Tissue samples from brain were processed as previously described (22). The expression of Mn-SOD, HO-1, neuronal NO synthase (nNOS), IjB-a, COX-2, Il-1b, CD11b, Iba-1, and a-synuclein was quantified in the cytosolic fraction from brain tissues.…”

“…Immunohistochemical localization was performed as previously described (22). Sections were incubated overnight with one of the following primary antibodies (all dilutions in PBS): polyclonal anti-TH polyclonal antibody (1:250; Merck-Millipore), polyclonal anti-DAT (1:00; Santa Cruz Biotechnology), polyclonal anti-TH (1:250; Merck-Millipore), anti-MAP-2 (1:250; MerckMillipore), polyclonal anti-NGF (1:250; Santa Cruz Biotechnology), and polyclonal anti-a-synuclein (1:50; Santa Cruz Biotechnology).…”

Potential Therapeutic Targets of the Endocannabinoid System in Common Neurodegenerative Disorders and Organic Acidemias

“…Although the constitutive expression of the receptors in the CNS plays a vital and consistent role in physiology, the inducible expression can also be provoked with prior inflammatory insult. Currently, the connection between the ECS and neurological diseases is not entirely understood; nevertheless, copious information proposes ECS' hypofunction and overall dysregulation as the cause of some notorious symptoms of neurological diseases, especially when considering its neuroprotective and prohomeostatic functions, which drives the system as a whole to a potential link to mood and anxiety alterations, 78,79 major motor disorders such as PD or HD, 80,81 and other pathologies (Figure 1). Hence, most therapeutic approaches bet on pharmacological methodologies that alter the CB pathway or explore the endogenous increase in specific CB compounds that trigger desired responses.…”

Oral Palmitoylethanolamide Treatment Is Associated with Reduced Cutaneous Adverse Effects of Interferon-β1a and Circulating Proinflammatory Cytokines in Relapsing–Remitting Multiple Sclerosis

“…Since the 1990s, interest in the therapeutic potential of PEA has increased owing to the discovery of the effects of PEA in many preclinical paradigms for pain and chronic inflammation [2]. PEA has antinociceptive properties in several animal models [3][4][5], prevents neurotoxicity and neurodegeneration [6][7][8], and inhibits peripheral inflammation and mast cell degranulation [9,10]. These effects of PEA are not only observed when used as a drug (i.e., after direct administration) [11,12], but also when its endogenous levels are increased by blocking its catabolism [13].…”