Table 6.
Small molecule inhibitors of cathepsin B are efficacious for improving behavioral and pathological deficits in TBI and TBI-related animal models.
| Disease model | Compound (method) | Compound effects (relative to control) |
Reference | ||
|---|---|---|---|---|---|
| Behavior | Pathology | Biomarkers | |||
| Trauma TBI | E64d (oral, A) | ↓ Motor deficits | Brain ↓ Lesion vol; neuronal death |
Brain ↓ Cat B; Bax |
(48) |
| CA-074Me (icv, B) | ↓ Memory deficits | Brain ↓ Lesion vol; neuronal death |
Brain ↓ Cat B act; t-Bid; Bax; mito cyt c; caspase 3 |
(94) | |
| z-DEVD-fmk (icv, A) | ↓ Motor and cognitive deficits | Brain ↓ Lesion vol; Neuronal death |
Brain ↓ Calpain I act; LDH; α-spectrin degradation |
(247) | |
| LHVS (icv, B) | ↓ NNS ↑ Grip strength |
Brain ↓ Edema; neuronal death |
Brain ↓ TNFα; IL-1β |
(248) | |
| Trauma SCC | E64d (iv, A) | nd | Spinal cord ↓ Reactive gliosis |
Spinal cord ↓ Calpain act; GFAP; caspase 3; DNA fragments |
(249) |
| Neuroexcitatory epilepsy | E64d (ip, B) | nd | ↓ Brain mossy fiber sprouting | Brain mRNA ↓ Cat B; PRG-1; PRG-3; PRG-5; ApoE; Clusterin; nSMase ↑ ANX7 |
(122) |
| CA-074Me (ip, B) | ↑ Neurological scores; learning ability | nd | Brain ↓ Cat B act; LC3II/LC3I; Beclin-1; Bcl-2; PRG-1 |
(111) | |
| Neuroexcitatory huntington disease | Z-FA-FMK (is, B/A) | nd | ↓ Brain lesion volume | nd | (112) |
| Pain | CA-074Me (it, B) | ↓ Inflammatory pain | nd | Microglia: ↓ mIL-1β; mIL-18β | (115) |
| Infectious brain meningitis | CA-074Me (ip, B and A) | nd | Improved Clinical score; ↓ CSF WBC; ICP | ↓ Brain IL-1β | (42) |
| Ischemia | E64c (ip, B) | nd | nd | ↓ Brain MAP2 degradation | (250) |
| CA-074 (iv, A) | nd | ↓ Brain neuronal death | ↓ Brain cat B | (108) | |
| CA-074; E64c (iv, A) | nd | ↓ Brain neuronal death | ↓ Brain cathepsin B activity | (109) | |
| CP-1 (iv, A) | ↓ Brain infarct volume | nd | (251) | ||
| CA-074, E64c (iv, A) | nd | ↓ Brain neuronal death | nd | (252) | |
| E64d (ip, B) | nd | Brain ↓ Infarct vol; neuronal death; Edema; vascular damage |
Brain: ↓ Cat B: Calpain I; Caspase 3; Vascular: ↓ Cat B; Calpain I; Caspase 3 |
(106) | |
| CP-1 (iv, A) | ↓ Neurological defects | ↓ Infarct vol. | Brain: ↓ Cat B act; Heat shock prot; Serum albumin; CRMP2 | (110) | |
| Cerebral aneurysm | NC-2300 (oral, A) | nd | Brain ↓ Aneurysms; ECM degradation |
Aneurysm: ↓ Cat B act; Cat K act; Cat S act ↓ Collagenase; ↑ Elastin |
(104) |
| Cerebral bleeding | CP-1 (iv, A) | ↓ Motor sensor deficits | Brain ↓ Tissue loss; neuronal death ↑ Neuronal proliferation |
Brain ↑ Synaptophysin; TUJI; Brd; VWF |
(253) |
| Inflammation rheumatoid arthritis | E64d (ip B/A) | ↓ Clinical symptoms | Joint ↓ pathology | Joint: ↓ IL-1β; IL-6 | (40) |
| Inflammatory pain and edema | K11777 (ip B and A) | ↓ Inflammatory pain | ↓ Edema; Necrosis; pathology |
↓ Cat B; Cat L; Cat S; Amylase act Spinal cord neurons: ↓ c-Fos |
(254) |
| CA-074Me (iv, B) | nd | ↓ Pathology; edema | ↓ Cat B act; Trypsin act; TAP; MPO act; Amylase act | (37) | |
| Neuro-degenerative AD transgenic APPSwe | E64 (ip) | ↓ Memory deficits | ↑ Long-term potentiation | Brain Aβ(1-40/42) no change | (255) |
| Neuro-degenerative AD transgenic APPLon |
E64d (oral) E64d (oral) |
↓ Memory deficits | ↓ Brain Aβ plaque ↓ Brain pGlu Aβ plaque |
Brain ↓ Aβ(1-40/42); CTFβ ↑ sAPPα ↓ Brain pGlu Aβ(3-40/42) |
(256) (141) |
| Neurodegenerative MS EAE |
LHVS (ip) | nd | Improved clinical score ↓ Spinal cord leukocyte infiltration ↑ Age of onset |
↓ Immune cell markers (MHC-II, CD69 CD4+ cells) | (146) |
B, A, treated before and after inducing pathology, respectively; icv, intracerebroventricular; ip, intraperitoneal; iv, intravenous; is, intrastriatal; it, intrathecal; NNS, neurological severity score; ICP, intracranial pressure; CSF WBC, cerebrospinal fluid white blood cells; PRG-2, 3, 5, plasticity related gene 2, 3, 5, respectively; ApoE, apolipoprotein E; sMase 2, spingomyelinase 2; ANX7, annexin 7; Clusterin, apolipoprotein J; MAP2, microtubule-associated protein; CRMP2, collagen response mediator protein 2; TUJ1, Class III Beta-tubulin; BrdU, bromodeoxyuridine; VWF, von Willebrand factor; MPO, myeloperoxidase; TAP, trypsinogin activation peptide; GDPH, glycerol-3-phosphate dehydrogenase; ALT, alanine aminotransferase; MIP2, macrophage inflammatory protein; KC, chemokine (CXC) ligand; αSMA, α smooth muscle actin; TGFβ, transforming growth factor β; COL1A1, collagen α1(I); TIMP, tissue inhibitor of metalloproteinases. Blue and tan colors indicate significant effects on behavior and pathology, respectively, by cathepsin B gene deletion.