Molecular mechanisms underlying the neuroprotection of environmental enrichment in Parkinson's disease

Abstract

Parkinson's disease is the most common movement disorder, affecting about 1% of the population over the age of 60 years. Parkinson's disease is characterized clinically by resting tremor, bradykinesia, rigidity and postural instability, as a result of the progressive loss of nigrostriatal dopaminergic neurons. In addition to this neuronal cell loss, Parkinson's disease is characterized by the accumulation of intracellular protein aggregates, Lewy bodies and Lewy neurites, composed primarily of the protein α-synuclein. Although it was first described almost 200 years ago, there are no disease-modifying drugs to treat patients with Parkinson's disease. In addition to conventional therapies, non-pharmacological treatment strategies are under investigation in patients and animal models of neurodegenerative disorders. Among such strategies, environmental enrichment, comprising physical exercise, cognitive stimulus, and social interactions, has been assessed in preclinical models of Parkinson's disease. Environmental enrichment can cause structural and functional changes in the brain and promote neurogenesis and dendritic growth by modifying gene expression, enhancing the expression of neurotrophic factors and modulating neurotransmission. In this review article, we focus on the current knowledge about the molecular mechanisms underlying environmental enrichment neuroprotection in Parkinson's disease, highlighting its influence on the dopaminergic, cholinergic, glutamatergic and GABAergic systems, as well as the involvement of neurotrophic factors. We describe experimental pre-clinical data showing how environmental enrichment can act as a modulator in a neurochemical and behavioral context in different animal models of Parkinson's disease, highlighting the potential of environmental enrichment as an additional strategy in the management and prevention of this complex disease.

Keywords: Parkinson’s disease; acetylcholine; brain-derived neurotrophic factor; dopamine; environment enrichment; gamma-aminobutyric acid; glial cell line-derived neurotrophic factor; glutamate; molecular mechanisms.

Figure 1

Effects of environmental enrichment on the dopaminergic system. Dopamine is synthesized from tyrosine by tyrosine hydroxylase to levodopa (L-DOPA), and subsequent decarboxylation to dopamine. The effects of dopamine are mediated by dopamine receptors. To stop signaling, extracellular dopamine is either removed through neuronal reuptake by dopamine transporter (DAT) or metabolized by monoamine oxidase B (MAO-B) and catechol-O-methyl transferase (COMT) in 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), respectively. Environmental enrichment upregulates tyrosine hydroxylase expression and DOPAC and HVA levels in DP models (positive sign). Moreover, environmental enrichment downregulates the levels of DAT and decreases DAT-binding through increases of brain-derived neurotrophic factor (BDNF) (positive sign). Furthermore, environmental enrichment upregulates glial cell line-derived neurotrophic factor (GDNF) and nerve growth factor (NGF) (positive sign), which produces its effect through PI3K pathway.

Figure 2

Effects of environmental enrichment on the cholinergic system. Acetylcholine (ACh) is synthesized in neurons from choline and acetyl-coenzyme A by the enzyme acetyltransferase (ChAT). ACh is loaded into synaptic vesicles and is released from nerve terminals. The effects of ACh are mediated by the activation of ionotropic or metabotropic receptors as muscarinic ACh receptor (M1R). ACh is degraded into choline and acetate by the enzyme acetylcholinesterase. Stressful environment upregulates acetylcholinesterase enzyme and environmental enrichment downregulates it (minus sign). Also, environmental enrichment upregulates acetyltransferase enzyme expression (positive sign) and downregulates M1R expression (minus sign).

Figure 3

Effects of environmental enrichment on the glutamatergic system. Glutamate is synthesized from glutamine in a reaction catalyzed by glutaminase. Glutamate is then packaged into synaptic vesicles by the vesicular glutamate transporter (VGLUT) and is released from nerve terminals. The effects of glutamate are mediated by the activation of ionotropic (iGluR as N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA)) and metabotropic receptors like mGluR5. Glutamate is cleared from the synapse through excitatory amino acid transporters (EAAT) present on neighboring glial cells and neurons. Within the glial cell, glutamate is converted to glutamine by glutamine synthetase and the glutamine is subsequently released by system N transport (SN1) and taken up by neurons through system A transport (SAT2). Environmental enrichment upregulates glutamate basal levels and AMPA and NMDA expression (positive sign). Moreover, it increases BDNF levels and pyramidal cell dendritic branching through mGluR5 activation (positive sign). BDNF: Brain-derived neurotrophic factor; CREB: CRE binding protein; PKC: protein kinase C.

Figure 4

Effects of environmental enrichment on the GABAergic system. GABA is synthesized in the pre-synaptic terminal from glutamate by glutamic acid decarboxylase (GAD) enzymes, GAD65 and GAD67. GABA is loaded into synaptic vesicles by a vesicular neurotransmitter transporter and is released from nerve terminals. The effects of GABA are mediated by the activation of ionotropic or metabotropic receptors. Environmental enrichment downregulates basal GABA concentrations and GABAergic inhibition (minus sign).