Table 1 List of potential mitochondria-targeted intranasal compounds used in preclinical studies
Compound name | Compound class | Chemical properties | Pharmacokinetic information | Tested CNS diseases | Mechanism of action (in relation to mitochondria) |
|---|---|---|---|---|---|
Nicotinamide mononucleotide (NMN)/Nicotinamide adenine Dinucleotide (NAD) [58] | Empirical Formula: C21H28N7O14P2 Therapeutic: Cofactor/Coenzyme | PH: Base logP: 6.38 pKa: -1.2 (Predicted) | Delicate molecule, oral consumption may destroy it NAD half-life 1- 2 h | Transient Focal Ischemia, TBI, Neurodegenerative diseases | Restores mitochondrial function via participation TCA cycle and oxidative phosphorylation |
N-acetylcysteine amide (NACA) [59] | Empirical Formula: C5H10N2O2S, amide of NAC Therapeutic: Antioxidant, Anti-inflammatory | PH: Base logP: -0.44 pKa: 9.52 | BBB permeant, half‐life 6.25 h [60] | TBI, Acute Cognitive Dysfunction, PD | Reduces oxidative stress, improves mitochondrial bioenergetics, and maintains mitochondrial glutathione content |
SKQ1/Mito Q [61] | Empirical Formula: C36H42BrO2P/C37H44O4P Therapeutic: Antioxidant | PH: logP: pKa: | Bioavailability limited by intracellular metabolism [62] | TBI, AD PD | Selectively blocks mitochondrial oxidative damage and prevents cell death |
Empirical Formula: C21H20O6 Therapeutic: Anti-inflammatory, Anti-tumor, Antioxidant | PH: Neutral logP: 3.62 pKa: 9.06 | Poor oral absorption, IN delivery enhanced brain-uptake efficiency | AD, Brain Inflammation [68], Dementia | Protects mitochondria from oxidative damage and attenuates apoptosis | |
Empirical Formula: C21H20O6, polyphenolic phytoalexin Therapeutic: Antioxidant | PH: Neutral logP: 2.57 pKa: 8.49 | High oral absorption, but low bioavailability [71] | AD, Autism, TBI, Brain Ischemia [72] | Induces mitochondrial biogenesis through SIRT pathway [72] | |
Empirical Formula: C14H22N2O2, carbamate ester Therapeutic: Cholinergic agent | PH: Acid logP: 2.45 pKa: 8.89 | Half-life 1.5 h, and volume distribution—1.8–2.7 L/kg [75] | AD, Dementia, PD ETC [76] | Enhances mitochondrial ETC function, increases enzymatic activities of diverse complexes and oxidative capacity of the ETC [76] | |
Cyclin D1 [77] | Empirical Formula: C43H71N9O11S2 Therapeutic: Cell cycle regulator | PH: Acid logP: -0.3 pKa: | Half-life < 30 min [78] | TBI | Regulates mitochondrial function by coordinating metabolic substrate utilization within the cell [77] |
Empirical Formula: C23H36O7 Therapeutic: HMG-CoA Reductase Inhibitor | PH: Acid logP: 3.5 pKa: 4.3 | Water Soluble, half-life ~ 12 h [81] | TBI, AD [82] | Attenuates AGEs-induced mitophagy via inhibition of ROS generation in the mitochondria [83] | |
Caspase-1 Inhibitor Boc-D-CMK [84] | Empirical Formula: C17H22ClNO5 Therapeutic: Caspase-1 Inhibitor | PH: logP: 2.7 pKa: | AD, Multiple Sclerosis, Neurodegenerative diseases [85] | Decreases mitochondrial dysfunction, and attenuates caspase-3-dependent apoptotic pathway [86] | |
Pentoxifylline [87] | Empirical Formula: C13H18N4O3, a xanthine derivative Therapeutic: Phosphodiesterase inhibitor (Vasoactive) | PH: Base logP: 0.3 pKa: 19.64 | Parental compound half-life- 0.4–0.8 h, and it’s metabolites half-life- 1–1.6 h [88] | It affects the Nrf2 antioxidant response elements pathway; thus, could help treat TBI or AD [89] | Reverses oxidative mitochondrial defect in claudicating skeletal muscle [90] |
Ketamine [91] | Chemical: C13H16ClNO Therapeutic: Anesthesia | PH: Acid logP: 4.7 pKa: 2.2 | Distribution half-life is about 7 -11 min, and the elimination half-life is about 2.5–3 h [92] | TBI [93] | Ketamine restores levels of malondialdehyde, glutathione peroxidase and superoxide dismutase |
Tetrandrine [94] | Chemical: C38H42N2O6, a bis-benzylisoquinoline alkaloid Therapeutic: Calcium Channel Inhibitor | PH: Base logP: 5.55 pKa: 8.28 | Very low bioavailability, which is why intranasal delivery is an essential route | Ischemic Stroke, TBI [94] | Prevents doxorubicin-induced mitochondrial impairment [95] |
Insulin [96] | Empirical Formula: C257H383N65O77S6 Therapeutic: Peptide hormone | PH: logP: pKa: | Half-life 4–6 min | Increases expression of mitochondrial proteins, oxidative enzyme activity and ATP synthesis in muscle [97, 99, 100] | |
Geraniol [101] | Empirical Formula: C10H18O is a monoterpene Therapeutic: Anti-inflammatory, antioxidant | PH: Neutral logP: 2.89 pKa:16.33 | BBB permeable, Half-life 12 min [102] | Cerebral Ischemia, PD, Neurological diseases [103] | Increases cell viability, preserved mitochondria membrane potential and improves the level of mitochondrial complex 1 [104] |
Muscone [105] | Empirical Formula: C16H30O Therapeutic: Neuroprotectant | PH: logP: pKa: | BBB permeable [106], IN delivery serves as a route for rapid drug entry into the brain [107] | TBI, Ischemia injury Spinal Cord Compression [106] | |
Empirical Formula: C36H60N10O12 Therapeutic: growth factor | PH: Acid logP: -2.6 | Well tolerated after IN or IV administration [112] | AD, Stroke, Hypoxia [111] | Inhibition of programmed cell death and correction of mitochondrial dysfunction | |
Apelin-13 [113] | Empirical Formula: C69H111N23O16S Therapeutic: Anti-inflammatory [113] | PH: logP: pKa: | Half-life 5–8 min [113] | Brain Ischemia [113] | Prevented serum deprivation (SD)-induced mitochondrial depolarization and apoptotic events [114] |
Quercetin [115] | Empirical Formula: C15H10O7 is a polyphenolic flavonoid Therapeutic: Anti-inflammatory, Neuroprotectant | PH: Neutral logP: 1.81 pKa:6.44 | Poor solubility, poor oral absorption | AD, Brain Ischemia | Modulates pathways associated with mitochondrial biogenesis and mitochondrial membrane potential |
Empirical Formula: C12H14O2 Therapeutic: Nutraceuticals, Antioxidants | PH: Weak Base logP: 3 pKa: 14.18 | Fat-soluble, half-life 11.84 h | Ischemic Stroke, TBI, Neurodegenerative diseases | Prevents Oxidative damage and reduces mitochondrial dysfunction | |
Gallotannin [118] | Empirical Formula C27H24O18 is a polyphenolic compound Therapeutic: PARG inhibitor | PH: Acid logP: 4.73 pKa: 7.61 | Poor bioavailability, large size, high affinity to plasma proteins | Neurodegenerative diseases, Brain Ischemia [118] | PARP inhibition protects mitochondria and reduces ROS production [118] |
Progesterone [119] | Empirical Formula: C21H30O2 is a steroid hormone Therapeutic: Endogenous sex hormone | PH: Base logP: 3.58 pKa:18.92 | Low oral bioavailability, half-life is 5–20 min [120] | Stroke, TBI, Spinal Cord Trauma, Central and peripheral neuropathies | Stimulates mitochondrial biogenesis and enhances mitochondrial functional efficiency and increased metabolic rates [121] |
Empirical Formula: C15H18N2O, sesquiterpene alkaloid Therapeutic: Acetylcholinesterase Inhibitor | PH: Base logP: 0.833 pKa: 7.7 | Crosses BBB, half-life 10–14 h [124] | AD, Epilepsy, TBI | Attenuates apoptosis by inhibiting the mitochondria–caspase pathway directly and indirectly [125] | |
Ginsenoside Rg3 (GRg3) [126] | Empirical Formula: C42H72O13 Therapeutic: Natural steroid glycosides | PH: Base logP: 2.27 pKa: 12.9 | Half-life 16 min [127] | Neurodegenerative disease, TBI, Brain Ischemia | Antioxidant, triggers mitochondrial rejuvenation |