TABLE 1.
Potential therapeutic agents for cerebrovascular diseases.
| Drug class | Drug name | Disease/model | Target | Function/outcome | References | Clinical trial |
|---|---|---|---|---|---|---|
| Ion transporter cascade inhibitors | Bumetanide (BTN or BMT or BUM) | Ischemic Stroke, AD, VCID, Neonatal seizures, Autism | NKCC1 and NKCC2 | • Potent loop diuretic | Bhuiyan et al., 2017; Boyarko et al., 2023; Graber-Naidich et al., 2023a, Graber-Naidich et al., 2023b; Kharod et al., 2019; O'Donnell et al., 2004; Savardi et al., 2021; Sivakumaran and Maguire, 2016; Taubes et al., 2021; Yu et al., 2018 | FDA-approved potent loop diuretic |
| • Decrease acute ischemia- or chronic hypoperfusion-induced white matter damage, astrogliosis, brain edema and infarction | Drug candidate for treating APOE4-related AD | |||||
| • Improves neurological and cognitive functions | Phase IIa (NCT06052163) | |||||
| BUM13 (Bumepamine, lipophilic benzylamine derivative of bumetanide) | Epilepsy and Kidney diseases | NKCC2A | • Penetrate the BBB | Brandt et al., 2018; Lykke et al., 2015; Romermann et al., 2017 | Preclinical | |
| • Inhibit NKCC2A | ||||||
| • Potentiate the anti-seizure effect of phenobarbital | ||||||
| STS5/BUM5 (N,N-dimethylaminoethylester of bumetanide/DIMAEB) | Ischemic stroke, Epilepsy and Kidney diseases | NKCC1 | • Reduce ischemic infarction and cerebral edema | Auer et al., 2020; Boyarko et al., 2023; Erker et al., 2016; Huang et al., 2019; Johne et al., 2021; Romermann et al., 2017; Tollner et al., 2014 | Preclinical | |
| • Improve cognitive function | ||||||
| • Penetrate the BBB | ||||||
| • Potentiate the anti-seizure effect of phenobarbital | ||||||
| STS66 | Ischemic stroke | NKCC1 | Reduce stroke-induced hemisphere swelling, infarction and improve neurological functions | Huang et al. (2019) | Preclinical | |
| ZT-1a | Ischemic Stroke PSD, VCID | SPAK | • Reduce stroke-induced infarction, swelling, white matter lesions and improve neurological functions | Bhuiyan et al., 2024a; Bhuiyan et al., 2022; Zhang et al., 2020 | Preclinical | |
| • Reduce astrogliosis, oligodendrocyte death, WML and improve cognitive functions | ||||||
| • Reduce C3d + A1 cytotoxic reactive astrocytes while preserving S100A10+GFAP + homeostatic A2 astrocytes | ||||||
| ZT-1a derivatives (1c, 1day, 1g and 1h) | Ischemic Stroke and PSD | SPAK | • Decrease ischemic brain lesion | Bhuiyan et al. (2023) | Preclinical | |
| • Preserve white matter integrity | ||||||
| • Improve neurological outcome | ||||||
| Closantel | Ischemic Stroke | SPAK | • Reduce stroke-induced infarction and hemisphere swelling | Gloeckner et al., 2010; Zhang et al., 2020 | FDA-approved broad-spectrum salicylanilide veterinary antiparasitic drug for a variety of types of animals Preclinical (Ischemic stroke) | |
| WNK463 | Ischemic Stroke, hypertension | WNK | • Reduce blood pressure and regulates body fluid and electrolyte homeostasis | Yamada et al., 2016; Zhang et al., 2020 | Preclinicalß | |
| • No effect on stroke outcome | ||||||
| HOE642 (Cariporide) | Ischemic Stroke, VCID | NHE1 | • Attenuate astrogliosis, microglial activation, and demyelination | Liu et al., 2021; Metwally et al., 2023 | Preclinical | |
| • Improve white matter integrity and cognitive function | ||||||
| • Reduce stroke-induced brain infarction, swelling and improve neurological functions | ||||||
| GLP-1R agonists | NLY01 | PD and AD | Inhibits microglial secretion of inflammatory cytokines (IL-1α, TNFα, and C1q) cocktails | • Penetrate CNS and block pathologic α-synuclein-induced microglial activation | Park et al., 2021; Yun et al., 2018 | Phase I trial (NCT03672604) |
| • Protect against dopaminergic neuronal loss and cognitive deficits | NLY01-PD-1 (NCT04154072) | |||||
| • Attenuate A1 astrogliosis | Phase IIB Alzheimer’s study | |||||
| • Reduce pathologic oligomeric Aβ1-42-induced microglia activation | ||||||
| Semaglutide | Ischemic stroke and Dementia | Inhibits microglial secretion of inflammatory cytokines (IL-1α, TNFα, and C1q) cocktails | • Attenuate Iba-1+ microglia/macrophages, and C3d+/GFAP + A1 reactive astrocytes | Buie et al., 2019; Zhang et al., 2022; Zlokovic et al., 2020 | FDA approved GLP-1R agonist for T2D (EVOKE, NCT04777396 and EVOKE Plus, NCT0477740) | |
| • Reduce BBB damage, brain infarction, and improve neurological function | Phase III (SELECT NCT0357459) | |||||
| NLRP3 inflammasome inhibitor | MCC950 | Experimental autoimmune encephalomyelitis (EAE) | NLRP3 | • Reduce astrogliosis | Hou et al., 2023; Hou et al., 2020 | Preclinical |
| • Prevent EAE-induced demyelination | ||||||
| • Prevent transformation of cytotoxic A1 astrocytes and enhance protective A2 astrocytes | ||||||
| • Block microglial conversion to M1 microglia | ||||||
| JC-124 | Traumatic brain injury (TBI) and AD | NLRP3 | • Reduce number of Iba-1+ microglia/macrophages and Aβ deposition | Kuwar et al., 2019; Yin et al., 2018 | Preclinical | |
| • Decrease brain inflammation | ||||||
| • Attenuate expression of IL-1β, TNF-alpha, and iNOs | ||||||
| OLT1177 | AD | NLRP3 | Reduce microglial activation and improves cognitive deficits | Lonnemann et al. (2020) | Preclinical | |
| RRx-001 (Nibrozetone) | AD and PD | NLRP3 | • Penetrate blood-brain barrier | Jayabalan et al., 2023; Oronsky et al., 2023 | Phase I (BRAINSTORM NCT02215512) | |
| • Reduce chronic inflammation | ||||||
| Minocycline | Early brain injury (EBI) and ischemic stroke | NLRP3 | • Reduce the number of Iba-1+ microglial cells, IL-1β expression, and improve neurological functions | Hayakawa et al., 2008; Li et al., 2016; Lu et al., 2016; Sheng et al., 2018 | Phase II (NCT05367362) | |
| • Reduce IL-1β and IL-18 cytokines level and cerebral infract volume | ||||||
| Inflammatory cytokine inhibitors and antibodies | Rilonacept | Rheumatoid arthritis | IL-1 blocker | Reduce inflammation | Arnold et al. (2022) | FDA approved |
| Anakinra | Rheumatoid arthritis and stroke | IL-1R antagonist | Reduce secondary brain damage following spontaneous hemorrhagic stroke | Arnold, Yalamanoglu and Boyman (2022) | FDA approved Phase II “ACTION” (NCT04834388) | |
| Canakinumab (IL-1β neutralizing antibody) | rheumatoid arthritis | IL-1β neutralizing antibody | Reduce inflammation | Arnold, Yalamanoglu and Boyman (2022) | FDA approved | |
| IL-1R blocking antibody (anti-IL-1R) | AD | IL-1R blocking | • Alleviate cognitive deficits and markedly attenuates tau pathology | Kitazawa et al. (2011) | Preclinical | |
| • Inhibit amyloid-β formation by decreasing NF-κB transcriptional activity | ||||||
| • Inhibit inflammatory A1 astrocyte | ||||||
| anti–IL-18 IgG antibody | Rat model of vascular injury | Endogenous IL-18 neutralization | Inhibit cytokine production and NF-κB activation | Maffia et al. (2006) | Preclinical | |
| anti-C1q antibody (humanized anti-C1q antibody: ANX005) | LPS-induced neuroinflammation | C1q-neutralization | Reduce microglia-dependent synaptic loss and cognitive impairments | Lansita et al., 2017; Wu et al., 2023 | Phase I | |
| anti- TNFα antibody | Focal ischemic injury | TNFα neutralization | Provide neuroprotection against focal ischemic injury | Barone et al. (1997) | Preclinical | |
| Etanercept | AD | TNF-α inhibitors | Reduce activation of microglia and tau deposition | Ou et al. (2021) | Preclinical | |
| type-II human TNF-receptor to a transferrin receptor antibody | AD | TNFα neutralization | Reduce activation of microglia and tau deposition | Ou et al. (2021) | Preclinical | |
| Adalimumab | AD and VCID | TNF-α inhibition | • Reduce AD pathology and neurotoxicity by inhibition of NF-κB and improve cognitive deficits | Park et al., 2019; Xu H et al., 2021 | Preclinical | |
| • Decrease microglial activation | ||||||
| Aducanumab (Human monoclonal antibody Aduhelm) | Cerebral amyloid angiopathy (CAA) | Neutralizes oligomeric parenchymal forms of Aβ | Clear Aβ deposits from brains by recruiting Iba1-positive microglia and GFAP-positive astrocyte to Aβ plaques | Kong et al., 2022; Loomis et al., 2024; Ries and Sastre, 2016; Sevigny et al., 2016 | Accelerated FDA approved for AD (To be discontinued from 2024) | |
| Lecanemab (Humanized IgG1 antibody) | Early-stage AD | Aβ plaque | Reduce cognitive decline in early AD patients and Aβ plaque clearance | Prillaman, 2022; van Dyck et al., 2023 | Phase III (NCT03887455, NCT05925621, NCT04468659, NCT01767311, NCT05269394) | |
| Gantenerumab (anti-Aβ IgG1 monoclonal antibody) | Early-stage AD | Aggregated Aβ plaque | Reduce amyloid plaque in early AD (Did not show a significant impact on slowing clinical decline compared to a placebo at 116 weeks) | Bateman et al. (2023) | Phase III (NCT03444870, NCT03443973) | |
| Solanezumab | AD | Binds to the central epitope of monomeric amyloid-β and inhibits nucleation site for Aβ oligomerization | Increase peripheral elimination and solubilize amyloid-β in the cerebrospinal fluid to reestablish equilibrium (Did not demonstrate a reduction in cognitive decline compared to a placebo over a 240-week period in those with preclinical AD) | Sperling et al. (2023) | Phase III (NCT02008357) | |
| Choline-containing phospholipids | α-GPC | VCID, AD, and stroke | Transglutaminase | Improve learning and memory | Bramanti et al., 2008; Jeon et al., 2023; Parker et al., 2022; Salvadori et al., 2021; Tayebati et al., 2009 | FDA registered drug or nutraceutical (NCT05050604) |