The therapeutic role of minocycline in Parkinson's disease

Abstract

Minocycline, a semisynthetic tetracycline-derived antibiotic, has been shown to exert anti-apoptotic, anti-inflammatory, and antioxidant effects. Furthermore, there is rapidly growing evidence suggesting that minocycline may have some neuroprotective activity in various experimental models such as cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, Parkinson's disease (PD), Huntington's disease, and multiple sclerosis. In this perspective review, we summarize the preclinical and clinical findings suggesting the neuroprotective role of minocycline in PD.

Keywords: Parkinson’s disease; minocycline; neurodegeneration; neuroprotection.

Figure 1

Signaling mechanism involved in the neuroprotective actions of minocycline. AIF, apoptosis-inducing factor; BCL-2, B-cell leukemia/lymphoma 2; CCR-5, chemokine receptor type 5; CXCR3, chemokine (CXC motif) receptor; GluR, glutamate receptor; IP-10, interferon-inducible protein; MAPK, mitogen-activated protein kinase; MIP-1α, macrophage inflammatory protein 1α; MMP, matrix metalloprotease; NADPH, nicotinamide-adenine dinucleotide phosphate; PBR, peripheral benzodiazepine receptor; TNF, tumor necrosis factor; TUNEL, terminal deoxynucleotidyl transferase dUTP (2′-deoxyuridine, 5′-triphosphate).

Figure 2

Schematic representation of apoptosis and proposed sites of inhibition. 1. Free oxygen radicals, lipid peroxidation, and increased cytosolic calcium cause mitochondrial depolarization and an opening of the mitochondrial permeability transition pore on the inner membrane and an outer membrane pore in comprising products of the Bcl-2 family member, Bax. This causes the release of cytochrome c into the cytosol. 2. Cytochrome c combines with Apaf-1 forming a complex called the apoptosome. Procaspase 9 is eventually cleaved on the apoptosome forming active caspase 9 (initiator caspase). 3. Caspase 9 activates the executioner caspase 3. Caspase 3 causes DNA damage, PPAR-1 activation and finally apoptosis. 4. Caspase 8 is activated by the DISC, which is attached to the death receptor (belongs to the family of TNF receptors). 5. Minocycline inhibits cytosolic calcium overload, binds with free oxygen radicals (ROS), inhibits Bax, and activates Bcl-2 (antiapoptotic gene) 6. It also inhibits caspase 1, and activation and reactivation of caspase 3. 7. It stabilizes the mitochondrial membrane. ‘Activation’ is shown by black arrows and ‘inhibition’ is shown by red arrows. H⁺ Apaf-1, apoptotic protease activating factor; Bax, Bcl-2-associated X-apoptosis regulator; Bcl-2, B-cell leukemia/lymphoma 2; DISC, death-inducing signaling complex; DNA, deoxyribonucleic acid; PPAR-1, peroxisome proliferator-activated receptors-1.